CN108601844A - The dry type amorphization of mechanical and chemical activation by Milling balance between AP and mesoporous silica - Google Patents

The dry type amorphization of mechanical and chemical activation by Milling balance between AP and mesoporous silica Download PDF

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Publication number
CN108601844A
CN108601844A CN201680069926.3A CN201680069926A CN108601844A CN 108601844 A CN108601844 A CN 108601844A CN 201680069926 A CN201680069926 A CN 201680069926A CN 108601844 A CN108601844 A CN 108601844A
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China
Prior art keywords
particle
composite particles
pore volume
purposes
active constituent
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Inventor
H.H.赫菲尔
F.H.蒙苏尔
T.波利
Y.乔德里
K.罗布曼
T.拉德斯
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Grace GmbH
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Grace GmbH
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/16—Inorganic salts, minerals or trace elements
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • B01J35/633—
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B33/00—Silicon; Compounds thereof
    • C01B33/113—Silicon oxides; Hydrates thereof
    • C01B33/12—Silica; Hydrates thereof, e.g. lepidoic silicic acid
    • C01B33/18—Preparation of finely divided silica neither in sol nor in gel form; After-treatment thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2004/00—Particle morphology
    • C01P2004/50—Agglomerated particles
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2004/00—Particle morphology
    • C01P2004/60—Particles characterised by their size
    • C01P2004/61—Micrometer sized, i.e. from 1-100 micrometer
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2006/00—Physical properties of inorganic compounds
    • C01P2006/12—Surface area
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2006/00—Physical properties of inorganic compounds
    • C01P2006/14—Pore volume
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2006/00—Physical properties of inorganic compounds
    • C01P2006/16—Pore diameter
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2006/00—Physical properties of inorganic compounds
    • C01P2006/80—Compositional purity
    • C01P2006/82—Compositional purity water content

Abstract

The invention discloses particles.The invention also discloses the methods for preparing and using the particle.

Description

Mechanical and chemical activation is dry by Milling balance between AP and mesoporous silica Formula amorphization
Technical field
The present invention relates to suitable for being used as active constituent (such as medicine in a variety of processing of including but not limited to drug delivery Object) delivery agents particle.The invention further relates to the methods for preparing and using particle.
Background technology
It is continued for hardy developing suitable for being used as delivery agents in a variety of processing of including but not limited to drug delivery Porous particle.
Invention content
The present invention is by having found new porous inorganic particulate and preparation and solving this field using the method for new particle This demand.Compared to known active constituent (such as drug) delivery materials, particle of the invention surprisingly provides Excellent active constituent dissolution characteristics.The particle of the present invention can be prepared without using organic solvent.Therefore, Such as in the case where particle is used as drug delivery mechanism, the particle of gained not with may in particle remaining residual solvent Related problem.In addition, the method for the particle of the disclosed preparation present invention can be in several minutes of interior rather than a few hours or a couple of days Interior realization grain equilibrium, and relevant process problem is not used and handles with organic solvent.
Therefore, the present invention relates to porous inorganic particulates.In an exemplary embodiment, particle of the invention includes more Hole inorganic particle, the porous inorganic particulate have the total pore volume less than 1.0cc/gm that (i) is measured by mercury intrusion porosimetry, and (ii) the particle internal pore volume less than 0.3cc/gm measured by mercury intrusion porosimetry, wherein particle endoporus are defined as aperture and are less than Or it is equal toHole.
In a preferred embodiment, particle of the invention includes porous inorganic oxide particle, the porous, inorganic Oxide particle has the total pore volume less than 1.0cc/gm that (i) is measured by mercury intrusion porosimetry, and (ii) by pressure mercury gaging hole The particle internal pore volume less than 0.3cc/gm that method measures, wherein particle endoporus are defined as aperture and are less than or equal to Hole.
In another exemplary embodiment, particle of the invention includes composite particles, which includes：It is porous Inorganic particle, preferably porous inorganic oxide particle, and mechanically mix in the hole of inorganic oxide particles at least A kind of active constituent, wherein composite particles have the total pore volume less than 1.0cc/gm that (i) is measured by mercury intrusion porosimetry, and (ii) the particle internal pore volume less than 0.3cc/gm measured by mercury intrusion porosimetry, and wherein particle endoporus is defined as aperture It is less than or equal toHole.
The invention further relates to the methods for preparing porous inorganic particulate according to the present invention.The method for preparing the particle of the present invention It generally includes：Initial porous inorganic particulate with certain total pore volume is provided；By making particle in dry solvent-free environment In be subjected to being enough to realize grain equilibrium and form the mechanical force of newly exposed inner inorganic particle surface, make initial porous, inorganic The total pore volume of grain reduces；Then at least part of the porous inorganic particulate mechanically handled is made to consolidate or reunite again, To provide the porous inorganic particulate that is newly formed of the total pore volume different from the total pore volume of initial porous inorganic particulate.It is new to be formed Porous inorganic particulate total pore volume be smaller than or more than initial porous inorganic particulate total pore volume.It is preferred real at one It applies in scheme, the total pore volume of the porous inorganic particulate newly formed is less than the total pore volume of initial porous inorganic particulate.
In an exemplary embodiment, the method for preparing the particle of the present invention includes preparing the side of porous inorganic particulate Method, the method includes：Porous inorganic particulate is provided, which has is more than by what mercury intrusion porosimetry measured 1.0cc/gm (that is, using 0.01cc/gm as the arbitrary value for being more than 1.0cc/gm and being up to and include 10.0cc/gm of increment, such as 6.00cc/gm, or using 0.01cc/gm as the arbitrary model for being more than 1.0cc/gm and being up to and include the value of 10.0cc/gm of increment Enclose, for example, about 1.01cc/gm to about 9.99cc/gm) total pore volume, and (ii) be less than by what mercury intrusion porosimetry measured 3.0cc/gm (or using 0.01cc/gm as the arbitrary value for being more than 0cc/gm and being up to and include 3.0cc/gm of increment, such as 1.7cc/gm, or using 0.01cc/gm as any range for being more than 1.0cc/gm and being up to and include the value of 3.0cc/gm of increment, For example, about 1.01cc/gm to about 2.99cc/gm) particle internal pore volume, wherein particle endoporus is defined as aperture and is less than or waits InHole)；And particle is made to be subjected to being enough to be formed the machinery of porous inorganic particulate in dry solvent-free environment Power, the porous inorganic particulate have the total pore volume less than or equal to 1.0cc/gm measured by mercury intrusion porosimetry, and by pressing The particle internal pore volume less than 0.3cc/gm that mercury gaging hole method measures, wherein particle endoporus are defined as aperture and are less than or equal toHole.In a preferred method, porous inorganic particulate is porous inorganic oxide particle.
In another exemplary embodiment, the method for preparing the particle of the present invention includes preparing comprising at least one living The method of the compound porous inorganic particle of property ingredient.This method includes：(i) initial porous nothing with certain total pore volume is provided Machine particle and (ii) at least one active constituent；And particle and active constituent is made to be subjected to foot in dry solvent-free environment With realize grain equilibrium and formed newly exposed inner inorganic particle surface amount mechanical force；Then make mechanically to handle Porous inorganic particulate surface at least part consolidation or reunite again, to provide have mechanically mix in its hole Active constituent composite inorganic particle, wherein the total pore volume of the composite particles be different from initial porous inorganic particulate it is total Pore volume.The total pore volume of the composite particles newly formed be smaller than or more than initial porous inorganic particulate total pore volume.One In a preferred embodiment, the total pore volume of the composite particles newly formed is less than the total pore volume of initial porous inorganic particulate.
In an exemplary embodiment, the method for preparing composite particles includes：Porous inorganic particulate is provided, this is porous Inorganic particle has the total pore volume for being more than 1.0cc/ grams measured by mercury intrusion porosimetry；And make particle and at least one activity Ingredient is subjected to being enough to be formed the mechanical force of the amount of stephanoporate composite inorganic particle in dry solvent-free environment, the porous compound nothing Machine particle has mixes at least one of its hole active constituent, and wherein composite inorganic particle has is measured by mercury intrusion porosimetry Total pore volume less than or equal to 1.0cc/gm, and by hole body in the particle less than 0.3cc/gm of mercury intrusion porosimetry measurement Product, wherein particle endoporus are defined as aperture and are less than or equal toHole.
The purposes that the invention further relates to porous inorganic particulates in kinds of processes.In an exemplary embodiment, originally Invention is related to particle as by the purposes of the reagent at least one active delivery to environment, which to include porous Inorganic particle, the porous inorganic particulate have the total pore volume less than 1.0cc/gm that (i) is measured by mercury intrusion porosimetry, and (ii) the particle internal pore volume less than 0.3cc/gm measured by mercury intrusion porosimetry, wherein particle endoporus are defined as aperture and are less than Or it is equal toHole.
In another exemplary embodiment, the present invention relates to composite particles to be used as by least one active constituent It is delivered to the purposes of the reagent in environment, which includes：(i) inorganic particle, and (ii) mechanically mix it is inorganic There is (i) to be less than 1.0cc/ by what mercury intrusion porosimetry measured at least one of hole of particle active constituent, wherein composite particles The total pore volume of gm, and the particle internal pore volume less than 0.3cc/gm that (ii) is measured by mercury intrusion porosimetry.
In some desired embodiments, porous particle of the invention is used as drug delivery agent.It has been found that disclosed Particle surprisingly provides excellent drug delivery for treatment use, especially has by the way that drug to be dissolved into aqueous solution The drug of measured solubility relatively low in water.In other desired embodiments, particle is used as in each field Active delivery agent, including but not limited in dentistry or oral care, skin nursing, cosmetics, nutrition, agrochemicals and plant With catalyst application etc. in delivering active ingredients.
After having studied the detailed description of embodiment disclosed below and appended claims carefully, of the invention these And other feature and advantage will become obvious.
Description of the drawings
Fig. 1 shows the surface functional group of silica dioxide granule；
Fig. 2A-Fig. 2 D show (i)244FP silica (amplification factor 1000) is before the grinding (i.e. Fig. 2A, upper left side photo) and grinding after (i.e. Fig. 2 B, upper right side photo) photo, and (ii) show 244FP silica is before the grinding (i.e. Fig. 2 D, lower right curve graph) after (i.e. Fig. 2 C, lower left curve graph) and grinding The curve graph for accumulating pore volume, is such as measured by mercury injection method；
Fig. 3 A- Fig. 3 D show (i)XDP3050 silica (amplification factor 1000) is before the grinding The photo of (i.e. Fig. 3 B, upper right side photo) after (i.e. Fig. 3 A, upper left side photo) and grinding, and (ii) are shown XDP3050 silica before the grinding (i.e. Fig. 3 C, lower left curve graph) and grinding after (i.e. Fig. 3 D, lower right curve graph) Accumulation pore volume curve graph, such as measured by mercury injection method；
Fig. 4 show the brufen individually ground relative toThe Bu Luo that XDP silica is co-mulled and made into Fragrant X-ray diffraction studies data, described in following article embodiment 1；
Fig. 5 A- Fig. 5 B show the brufen individually ground relative toXDP silica is co-mulled and made into Brufen DSC heat score-curves, described in following article embodiment 1；
Fig. 6 show withThe combination for the brufen that XDP silica is co-mulled and made into is in various milling times Under X ray diffracting data；
Fig. 7 show brufen that (i) is individually ground relative to (ii) withXDP silica is ground altogether The brufen of mill and (iii) withThe dissolving for the brufen that XDP silica is co-mulled and made into, following article embodiment 1 Described in；
Fig. 8 show press power to comprising embodiment 1 composite particles (i.e. include withXDP titanium dioxides The composite particles for the brufen that silicon is co-mulled and made into) tablet tablet dissolved influence；
Fig. 9 show milling time to use regulation as described in Example 1 comprising with XDP The influence of the tablet dissolved of the composite particles for the brufen that 3050 silica are co-mulled and made into；
Figure 10-Figure 11 is shown and the photograph of the similar composite particles (amplification factor 1000) of those of formation in embodiment 1 Piece, i.e., comprising (1)244FP silica and brufen (Fig. 7), and (2)XDP 3,050 2 The composite particles of silica and brufen (Fig. 8)；
Figure 12 shows that milling time includes with 1 to use the regulation summarized such as embodiment 1:1 weight ratio or 1:5 Weight ratio withThe influence of the tablet dissolved of the composite particles for the brufen that XDP silica is co-mulled and made into；
Figure 13 show milling time to use the regulation summarized such as embodiment 1 comprising with various weight ratios withThe influence of the tablet dissolved of the composite particles for the brufen that XDP silica is co-mulled and made into；
Figure 14 shows that given carrier and storage include similar to the regulation as summarized in embodiment 1 to using The influence of the tablet dissolved of the composite particles for the brufen being co-mulled and made into various carriers；
Figure 15-Figure 16 shows the photo of the composite particles (amplification factor 1000) formed in example 2, that is, includes The composite particles of silica and ezetimibe；
Figure 17 show withThe combination for the ezetimibe that XDP silica is co-mulled and made into is ground various X ray diffracting data under time consuming；
Figure 18 show (i) with comprising withThe ezetimibe that XDP silica is co-mulled and made into it is compound Particle is formed by tablet, and (iii) commercially available ezetimibe tablet dissolving (as begged in embodiment 2 By)；And
Figure 19 A- Figure 19 B show display(i.e. Figure 19 A) and the grinding before the grinding of 244FP silica The curve graph of the accumulation pore volume of (i.e. Figure 19 B, the sample 17 of embodiment 3) later.
Detailed description
In order to promote the understanding to the principle of the invention, here to be the explanation of specific embodiments of the present invention, and use Language-specific describes the specific embodiment.It will be appreciated, however, that being not intended to limit the model of the present invention using language-specific It encloses.To the replacement of the discussed principle of the invention, further modification and such further application are considered involved by the present invention And field those of ordinary skill can normally occur.
It must be noted that unless the context clearly dictates otherwise, otherwise odd number as used herein and in the appended claims Form "one", "an" and "the" include plural reference.Thus, for example, referring to that " a kind of oxide " includes a variety of such oxygen Compound, and refer to that " oxide " includes referring to one or more oxides and its equivalent well known by persons skilled in the art Deng.
The amount, concentration, volume of ingredient, process warm in the modification such as composition used in describing disclosure embodiment Degree, process time, the rate of recovery or yield, flow velocity and similar value and their range " about " refer to can be for example by as follows The variation of the digital quantity of generation：It is typical to measure and handle regulation；Mistake caused by neglecting in these regulations；For implementing this The difference of the ingredient of method；And similar close consideration factor.Term " about " be also contemplated by due to specific initial concentration or The formulation aging of mixture and different amounts and due to mixing or handling the preparation with specific initial concentration or mixture Object and different amounts.It is modified in spite of by term " about ", claims appended hereto all includes the equivalent of this tittle.
As used herein, phrase " total pore volume " refers to (1) intergranular pores volume (body i.e. between particle of multiple particles Product) and (2) particle internal pore volume (i.e. intragranular pore volume) combination.In general, multiple intragranular many (if not complete Portion) " particle " include via Particle consolidation step such as ball milling or jet grinding or extrusion step and the particle of combination mechanically to each other Cluster.Therefore, multiple intragranular many single " particles " while there is intergranular pores volume and particle internal pore volume.In addition, Multiple particles also have the intergranular pores volume between multiple intragranular single " particles ".
As used herein, phrase " intergranular pores volume " refers to the volume between multiple intragranular particles, such as institute above It states, " intergranular pores volume " includes that the pore volume in (1) single " particle " (forms the hole body between the particle of particle clusters Product), the pore volume between (2) and single " particle " ".
As used herein, phrase " particle internal pore volume " refers to the hole body within the particle endoporus of particle in multiple particles Product.As used herein, " particle endoporus " is defined as aperture and is less than or equal toHole.
As used herein, phrase " dry solvent-free environment " refers to being free of solvent (i.e. any solvent intentionally added) simultaneously And it is typically free of the environment of any liquid, " dry solvent-free environment " may include certain journey in " dry solvent-free environment " The humidity of degree and/or the presence of water, but humidity and/or water exist as pollutant, rather than the group added as user Point.
As used herein, phrase " newly exposed inner inorganic particle surface " refers to table in previous unexposed inorganic particle Face is exposed via the mechanical step as described herein (for example, by grinding or extrusion step) for reducing pore volume.Phrase " newly exposed inner inorganic particle surface " is not related to the inner bore surface of inorganic particle, the inside of such as metal oxide particle Hole surface.Equally, as used herein, phrase " newly exposed inside active ingredient particle surface " refers to previous unexposed activity Ingredient granules inner surface is exposed via reduction step as described herein (for example, passing through grinding or extrusion step).
As used herein, " inorganic oxide " is defined as binary oxygen compound, wherein inorganic component be cation and Oxygen (oxide) is anion.Inorganic material includes metal, and may also comprise metalloid.Metal includes from the periodic table of elements Element those of on the left of the diagonal line that boron is drawn to polonium.Metalloid or semimetal include in those of line right side element.Nothing The example of machine oxide includes silica, aluminium oxide, titanium dioxide, zirconium oxide etc. and their mixture.
As used herein, " porous inorganic particulate " include by inorganic material or inorganic material (for example, metal, semimetal with And their alloy；Ceramics, including inorganic oxide；Deng) and organic material (such as organic polymer) combination, it is such as compound The particle that material is constituted, is substantially heterogeneous or homogeneous.For example, heterogeneous material compound include material pure mixture, Stratified material, core-shell structure copolymer etc..The example of homogeneous composite material includes alloy, organic-inorganic polymer hybrid material etc..Particle can For a variety of different symmetrical, asymmetric or irregular shapes, including chain, stick or lath shape.Particle can have different structures, Including amorphous or crystal structure etc..Particle may include having different compositions, size, shape or physical arrangement particle mixing Object or particle can in addition to different surface treatments all same.In the case where smaller particle agglomerates into larger particles, The porosity of grain can be in particle or intergranular porosity.In an exemplary embodiment, particle is all by inorganic material Such as inorganic oxide, sulfide, hydroxide, carbonate, silicate, phosphate composition, but desirably inorganic oxide, It can be formed via any of method, including but not limited to solution polymerization process (being such as used to form colloidal particles), continuous Flame hydrolysis (being such as used to form pyrolysable particles), gel method (being such as used to form gel particles), the precipitation method, spray-on process, Template, sol-gel method etc..
Can before processing (i.e. mechanical step), by autoclaving, flash drying, supercritical fluid extraction, etching or Similar method as former state or is changed according to of the invention and handles inorganic particle.Inorganic particle can be by organic material and/or nothing Machine material and combination thereof are constituted, and in an exemplary embodiment, inorganic particle is by such as inorganic oxygen of inorganic material The compositions such as compound, sulfide, hydroxide, carbonate, silicate, phosphate, but preferably inorganic oxide.Inorganic particle Can be a variety of different symmetrical, asymmetric or irregular shapes, including chain, stick or lath shape.Inorganic particle can have difference Structure, including amorphous or crystal structure etc..Inorganic particle may include thering is different compositions, size, shape or physical arrangement Particle mixture or particle can in addition to different surface treatments all same.Larger is agglomerated into smaller particle In the case of grain, the porosity of inorganic particle can be in particle and/or intergranular porosity.In an exemplary implementation scheme In, inorganic particle is by structures such as inorganic material inorganic oxide, sulfide, hydroxide, carbonate, silicate, phosphate At, but preferably inorganic oxide.Suitable porous inorganic oxide granular materials include organic material and inorganic material or Their impurity.
As used herein, term " crystal " refers to that its composed atom, molecule or ion are aligned to along all three directions The solid material of the orderly pattern extended, can be measured by X-ray diffraction method or differential scanning calorimetry.
As used herein, term " amorphous " refers to that its composed atom, molecule or ion are aligned to along all three sides To the solid material of the random unordered pattern of extension, can be measured by X-ray diffraction method or differential scanning calorimetry.
As used herein, phrase " grain equilibrium " refers to that given particle (or aggregate of particle) experience is in situ from crystalline state Amorphization is the time point of amorphous state.Once by the energy of threshold quantity (for example, (i) particle and particle friction and (ii) The friction energy of particle and the form of equipment friction) the given reaction vessel comprising grain fraction is introduced (for example, grinding container or crowded Go out container) in, " grain equilibrium " just occurs.For example, in some embodiments, when the mechanical agitation of application is kept constant When, " grain equilibrium " introduces rate in the stress and strain of grinding/extrusion and is equal to the stress and strain introducing rate of compacting (i.e. most Whole particle is formed) when occur.In some embodiments, " grain equilibrium " is indicated by following graininess and time：With first The particle of beginning average particle size has been exposed to desired mechanical agitation amount, to which (1) causes initial average particle size initially to reduce, and (2) the smaller particle consolidation with newly exposed particle surface for subsequently resulting in gained, has final average particle size to be formed Final particle, the final average particle size in several cases be more than initial average particle size.
As used herein, term " pore-size distribution " refer to porous inorganic particulate representative volume in each aperture it is relatively rich Degree.As used herein, " mean pore sizes " are following apertures：Less than under the aperture, 50% particle internal pore volume is present in 20 angstroms To 600 angstroms of hole.Pore-size distribution for example (can be purchased from Micromeritics Instrument using Autopore IV 9520 Corp. it) is measured by mercury injection method.
As used herein, term " active constituent " include but not limited to active pharmaceutical ingredient (API), agricultural component (such as Insecticide, fungicide, herbicide, fertilizer etc.), food or feed ingredient (such as nutriment, vitamin etc.) or they Any combinations.In some desired embodiments, " active constituent " includes following active pharmaceutical ingredient (API)：Pharmacology is provided Activity or in other ways diagnosis, healing, alleviation, treat or prevent disease in terms of have direct effect, or in the extensive of the mankind There is direct effect in terms of multiple, amendment or change physiological function.Even if this includes the poor material of dissolubility, but its may also comprise can Material within the scope of dissolubility is included in BCS (biopharmaceutics categorizing system (Biopharmaceutical Classification System)) in those of list, it is water-soluble and penetrate that the BCS is that a kind of drug (APS) is based on its The degree of permeability (high or low) of gastrointestinal tract wall (especially intestines) is divided into the sorting technique of four classes.In this regard, this four class It is：(I classes) highly dissoluble and high osmosis drug, (II classes) low-solubility and high osmosis drug, (Group III) highly dissoluble and Hypotonicity drug, and (IV classes) low-solubility and hypotonicity drug.
As used herein, term " dissolving " means that solid, liquid or gas form the process of solution in a solvent.In order to molten Solid is solved, which is related to lattice and/or solid structure resolves into single ion, atom or molecule, and they are transported to In solvent.The rate of dissolution of bioactive materials (such as API) is drug release and measures the measurement of vivo biodistribution utilization rate.
As used herein, term " BET granule surface areas " is defined as referring to such as by Bu Lunuo-Ai Meite-Teller The granule surface area that (Brunauer Emmett Teller) nitrogen adsorption method measures.
As used herein, term " molecular weight " is defined as referring to mole matter of the individual molecule of specific compound or polymer Amount.
Discussed in following article embodiment, porous inorganic particulate may include a variety of inorganic material, including but not limited to Aluminosilicate magnesium, calcium phosphate, calcium carbonate and inorganic oxide, such as silica, aluminium oxide, zirconium oxide, porosity-controllable Glass or their mixture.In a desired embodiment, inorganic oxide particles include silica.Suitably Silica includes but not limited to silica gel, precipitated silica, pyrogenic silica and colloidal silicon dioxide.Suitable dioxy SiClx further includes but is not limited to during silica dioxide granule is formed through organic formwork (such as surfactant), subsequent high temperature It is pyrolyzed the ordered mesoporous silica prepared with " burn-up " organic matter.When inorganic oxide particles include silica, particle The silica for including desirably has at least about 93.0 weight %SiO of the total weight based on the particle2Or at least about 93.5 Weight %SiO2, at least about 94.0 weight %SiO2, at least about 95.0 weight %SiO2, at least about 96.0 weight %SiO2, at least About 97.0 weight %SiO2Or at least about 98.0 weight %SiO2Up to 100 weight %SiO2Purity.
It may include any of active constituent for the active constituent in the composition of the present invention.In some embodiments In, active constituent includes at least one active pharmaceutical ingredient (API).In some embodiments, active constituent includes group each other Two or more active pharmaceutical ingredients (API) closed.In some embodiments, API includes biopharmaceutics categorizing system Those of the II or IV classes of (Biopharrnaceutics Classification System, BCS) (FDA).Exemplary API Including but not limited to Atorvastatin, amiodarone, Candesartan Cilexetil, Carvedilol, bisulfate clopidogrel, Dipyridamole, Epsartan mesylate (eposartan mesylate), eplerenone, ezetimibe, felodipine (felodipme), Furosemide, Isradipine, Lovastatin, metolazone, nicardipine, Nisoldipine, olmesartan medoxomil, propafenone hydrochloride, quinoline That Puli (ginapril), Ramipril, Simvastatin, Telmisartan, Trandolapril, Valsartan and other cardiac vascular activity medicines Object；Acyclovir, adefovirdipivoxil, Aldoforwe ester, anphotericin, anpunave, Cefixime, cefotaxime, clarithromycin, Clotrimazole, efavirenz, Ganciclovir, Itraconazole, Norfloxacin, nystatin, Ritonavir, inverase and other anti- Infection medicine, including antibacterium, antiviral, antimycotic and anti-parasite medicine；Cis-platinum, carboplatin, docetaxel, Etoposide, Exemestane, idarubicin, Irinotecan, melphalan, mercaptopurine, mitiane, taxol, valrubicin, vincristine and use In the other medicines of oncology；Imuran (azthioprine), tacrolimus, ring born of the same parents element, Elidel, sirolimus With other immunosuppressive drugs；Clozapine, Entacapone, fluphenazine, meter Pa Ming, Nefazodone, Olanzapine, Paxil, Pimoxide, Sertraline, triazolam, Zaleplon, siprasidone and Risperidone, carbamazepine and be used for CNS indications Other medicines；Danazol, Medroxyprogesterone, estradiol, Raloxifene, silaenafil, Tadalafei, testosterone, is cut down dutasteride That non-sum of ground is used for the other medicines of healthy reproduction；Celecoxib, agit, eletriptan, methylsulphur acid dihydride Ergotin, gynergen, Nabumetone, brufen, Ketoprofen, triamcinolone, Triamcinolone acetonide and it is other anti-inflammatory and only Pain medicine；Bosentan, budesonide, decarboxylation chlorine thunder, Fexofenadine fourth, Fluticasone, Loratadine, Mometasone, former times naphthoic acid Sha Meite Sieve, Triamcinolone acetonide, zafirlukast and the other medicines for breathing indication；And Dronabinol, famotidine, glibenclamide, Hyoscyamine (hyoscyramine), Accutane, megestrol acetate, aminosalicylic acid, modafinil (modafmil), Mosapride, Nimodipine, fluphenazine, Propofol, ulcerlmin, Sa Li polyamines, trizaidiline hydrochloride and for each The other medicines of kind indication (particularly including gastrointestinal disease, diabetes and skin disease indication).In other embodiments, API includes that ezetimibe glucosiduronic acid, Tadalafei, fenofibrate, danazol, Itraconazole, carbamazepine, sallow are mould Element, Nifedipine or any combination of them.
The other additional embodiment of the present invention is described below.It should be pointed out that any implementation disclosed herein In scheme by endpoint state numberical range include included in the range it is all number (for example, the range of about 1 to about 5 Including 1,1.5,2,2.75,3,3.80,4 and any range 5) and in the range (for example, the pact in 1 to 5 range 1.5 to about 3.78 range).
Additional embodiment：
Porous inorganic particulate
Porous inorganic particulate have (i) by mercury intrusion porosimetry measures less than 1.0cc/gm (or using 0.01cc/gm as increment The arbitrary value for being more than 0cc/gm and being up to and include 1.0cc/gm, such as 0.32cc/gm, or using 0.01cc/gm as increment Any range of the value of 1.0cc/gm, for example, about 0.30cc/gm to about 0.34cc/gm are up to and included more than 0cc/gm) Total pore volume, and (ii) by mercury intrusion porosimetry measure be less than 0.3cc/gm (or using 0.01cc/gm be increment be more than 0cc/ Gm is up to and includes the arbitrary value of 0.3cc/gm, such as 0.09cc/gm, or is more than 0cc/gm using 0.01cc/gm as increment Up to and include 0.3cc/gm value any range, for example, about 0.09cc/gm to about 0.11cc/gm) particle in hole body Product, wherein the particle endoporus is defined as aperture and is less than or equal toHole.Preferably, inorganic particle is porous nothing Machine oxide particle.
According to the porous inorganic particulate described in embodiment 1, wherein there is the particle (i) to be measured by mercury intrusion porosimetry Total pore volume more than 0cc/gm and less than about 0.98cc/gm, and (ii) by mercury intrusion porosimetry measures more than 0cc/gm and Particle internal pore volume less than about 0.28cc/gm.
Porous inorganic particulate according to embodiment 1 or 2, wherein there is the particle (i) to be surveyed by mercury intrusion porosimetry The total pore volume of fixed about 0.15cc/gm to about 0.93cc/gm, and about 0.05cc/gm that (ii) is measured by mercury intrusion porosimetry To the particle internal pore volume of about 0.24cc/gm.
Porous inorganic particulate according to any one of embodiment 1 to 3, wherein the particle has (i) by pressure mercury The total pore volume for the about 0.25cc/gm to about 0.40cc/gm that gaging hole method measures, and pact that (ii) is measured by mercury intrusion porosimetry The particle internal pore volume of 0.08cc/gm to about 0.16cc/gm.
Porous inorganic particulate according to any one of embodiment 1 to 4, wherein the particle has about 1.0 microns (μm) to about 100 μm (or with 0.1 μm 1.0 μm to about 100 μm for increment and include end value arbitrary value, such as 45.0 μm, or With 0.1 μm 1.0 μm to about 100 μm for increment and include end value value any range, for example, about 3.2 μm to about 50.1 μm) Average particle size.
Porous inorganic particulate according to any one of embodiment 1 to 5, wherein the particle have about 2.0 μm extremely About 60 μm of average particle size.
Porous inorganic particulate according to any one of embodiment 1 to 6, wherein the particle have about 40.0 μm extremely About 50.0 μm of average particle size.
Porous inorganic particulate according to any one of embodiment 1 to 7, wherein the particle includes to have on it The newly aggregate for the inorganic particle of exposed inner inorganic particle surface mechanically changed.
Composite particles
Composite particles, including porous inorganic particulate according to any one of embodiment 1 to 8 and mechanically mixing Enter at least one of the hole of inorganic particle active constituent, wherein there is the composite particles (i) to be surveyed by mercury intrusion porosimetry Hole body in the fixed total pore volume less than 1.0cc/gm, and (ii) particle less than 0.3cc/gm for being measured by mercury intrusion porosimetry Product.Preferably, porous particle is porous inorganic oxide particle.
Composite particles, including porous inorganic particulate and mechanically mixing at least one of the hole of the inorganic particle Active constituent, wherein the composite particles have (i) by mercury intrusion porosimetry measures less than 1.0cc/gm (or with 0.01cc/gm For the arbitrary value for being more than 0cc/gm and being up to and include 1.0cc/gm of increment, such as 0.32cc/gm, or it is with 0.01cc/gm Any range for being more than 0cc/gm and being up to and include the value of 1.0cc/gm of increment, for example, about 0.30cc/gm to about 0.34cc/ Gm total pore volume), and (ii) are less than 0.3cc/gm (or using 0.01cc/gm as the big of increment by what mercury intrusion porosimetry measured It is up to and includes the arbitrary value of 0.3cc/gm, such as 0.09cc/gm, or being more than using 0.01cc/gm as increment in 0cc/gm 0cc/gm be up to and include 0.3cc/gm value any range, for example, about 0.09cc/gm to about 0.11cc/gm) particle Internal pore volume, and the wherein described particle endoporus is defined as aperture and is less than or equal toHole.
According to the composite particles described in embodiment 10, wherein there is the composite particles (i) to be measured by mercury intrusion porosimetry Be more than 0cc/gm and the total pore volume less than about 0.98cc/gm, and (ii) by mercury intrusion porosimetry measures more than 0cc/gm And the particle internal pore volume less than about 0.28cc/gm.
Composite particles according to embodiment 10 or 11, wherein the composite particles have (i) by mercury intrusion porosimetry The total pore volume of the about 0.15cc/gm to about 0.93cc/gm of measurement, and about 0.05cc/ that (ii) is measured by mercury intrusion porosimetry The particle internal pore volume of gm to about 0.24cc/gm.
Composite particles according to any one of embodiment 10 to 12, wherein the composite particles have (i) by pressing The total pore volume for the about 0.25cc/gm to about 0.40cc/gm that mercury gaging hole method measures, and pact that (ii) is measured by mercury intrusion porosimetry The particle internal pore volume of 0.08cc/gm to about 0.16cc/gm.
Composite particles according to any one of embodiment 10 to 13, wherein the composite particles have about 1.0 μm To about 100 μm (or with 0.1 μm 1.0 μm to about 100 μm for increment and include end value arbitrary value, such as 45.0 μm, or with 0.1 μm for 1.0 μm to about 100 μm of increment and include end value value any range, for example, about 3.2 μm to about 50.1 μm) Average particle size.
Composite particles according to any one of embodiment 10 to 14, wherein the composite particles have about 2.0 μm To about 60 μm of average particle size.
Composite particles according to any one of embodiment 10 to 15, wherein the composite particles have about 40.0 μm To about 50.0 μm of average particle size.
Composite particles according to any one of embodiment 10 to 16, wherein the porous inorganic particulate includes new sudden and violent The aggregate of the inner inorganic particle surface of dew, and the inside of (ii) described at least one active constituent and the new exposure without Machine particle surface contacts.
Composite particles according to any one of embodiment 10 to 17, wherein at least one active constituent includes Newly exposed inside active constituent surface, and at least one active constituent is via the inner inorganic of new exposure described in (i) Particle surface, the inside active constituent surface of (ii) described new exposure or (iii) (i) and (ii) the two and the porous, inorganic Particle contacts.
Porous inorganic particulate and composite particles
Porous inorganic particulate according to any one of embodiment 1 to 8 or according to any one of embodiment 9 to 18 The composite particles, wherein the porous inorganic particulate has the average pore size of about 1.0nm to about 100.0nm.
Porous inorganic particulate according to any one of embodiment 1 to 8 or according to any one of embodiment 9 to 19 The composite particles, wherein the porous inorganic particulate has the average pore size of about 2.0nm to about 50.0nm.
Porous inorganic particulate according to any one of embodiment 1 to 8 or according to any one of embodiment 9 to 20 The composite particles, wherein the porous inorganic particulate has at least about 100m2/ g is up to 1500m2The BET of/g or bigger Granule surface area.
Porous inorganic particulate according to any one of embodiment 1 to 8 or according to any one of embodiment 9 to 21 The composite particles, wherein the porous inorganic particulate has at least about 100m2/ g is up to 500m2The BET particle surfaces of/g Product.
Porous inorganic particulate according to any one of embodiment 1 to 8 or according to any one of embodiment 9 to 22 The composite particles, wherein the porous inorganic particulate includes inorganic oxide particles.
Porous inorganic particulate according to any one of embodiment 1 to 8 or according to any one of embodiment 9 to 23 The composite particles, wherein the porous inorganic particulate includes metal oxide particle.In one embodiment, metal oxygen Compound particle is mesoporous metal oxide particle.
Porous inorganic particulate according to any one of embodiment 1 to 8 or according to any one of embodiment 9 to 24 The composite particles, wherein the inorganic particle includes silica dioxide granule.
Porous inorganic particulate according to any one of embodiment 1 to 8 or according to any one of embodiment 9 to 25 The composite particles, wherein the porous inorganic particulate includes with trade nameFP, AL1-FP are commercially available Silica dioxide granule, or with trade nameSilica dioxide granule commercially available XDP, and in any case Under, the silica dioxide granule has been mechanically changed to provide newly exposed inner silica silicon particle table on it Face.
Composite particles according to any one of embodiment 9 to 26, wherein at least one active constituent includes Granular active ingredients.
Composite particles according to any one of embodiment 9 to 27, wherein at least one active constituent includes Active pharmaceutical ingredient (API), agricultural chemicals, food additives or any combination of them.
Composite particles according to any one of embodiment 9 to 28, wherein at least one active constituent includes Active pharmaceutical ingredient (API) with tial crystalline structure.
Composite particles according to any one of embodiment 9 to 29, wherein at least one active constituent includes Active pharmaceutical ingredient (API) selected from brufen, ezetimibe or any combination of them.
Composite particles according to any one of embodiment 9 to 30, wherein (i) porous inorganic particulate and (ii) At least one active constituent is with about 100:1 to 1:Porous inorganic particulate in 100 ranges and at least one activity at The weight ratio divided exists.
Composite particles according to any one of embodiment 9 to 31, wherein (i) porous inorganic particulate and (ii) At least one active constituent is with about 10:1 to 1:Porous inorganic particulate in 10 ranges and at least one active constituent Weight ratio exist.
Composite particles according to any one of embodiment 9 to 32, wherein (i) porous inorganic particulate and (ii) At least one active constituent is with about 2:1 to 1:Porous inorganic particulate in 2 ranges and at least one active constituent Weight ratio exists.
Porous inorganic particulate according to any one of embodiment 1 to 8 or according to any one of embodiment 9 to 33 The composite particles, wherein the particle includes the less than about water of 5.0 weight % of the total weight based on the particle.
Porous inorganic particulate according to any one of embodiment 1 to 8 or according to any one of embodiment 9 to 34 The composite particles, wherein the particle includes the less than about water of 1.0 weight % of the total weight based on the particle.
Composite particles according to any one of embodiment 9 to 35, wherein the composite particles are substantially by described Porous inorganic particulate and at least one active constituent composition.
Composite particles according to any one of embodiment 9 to 36, wherein the composite particles are by the porous nothing Machine particle and at least one active constituent composition.
Porous inorganic particulate according to any one of embodiment 1 to 8 or according to any one of embodiment 9 to 37 The composite particles, wherein the porous inorganic particulate has mechanically to change by pressing via grinding or extrusion step What mercury gaging hole method measured is more than 0.3cc/gm, and preferably more than 1.0cc/gm by what mercury intrusion porosimetry measured (that is, or be more than 0.3cc/gm is up to and includes the arbitrary value of 15.0cc/gm, and preferably more than 1.0cc/gm is up to and includes 10.0cc/gm Arbitrary value) total pore volume porous inorganic particulate and formed.
The method for preparing porous inorganic particulate
The method for preparing the porous inorganic particulate according to any one of embodiment 1 to 8, the method includes：It carries For initial porous inorganic particulate, the initial porous inorganic particulate has the total pore volume measured by mercury intrusion porosimetry；And make The particle is subjected to being enough to be formed in dry solvent-free environment the mechanical force of the amount of newly exposed inner inorganic particle surface, Then allow at least part of the particle to consolidate or reunite again, be less than the initial porous, inorganic to form total pore volume The porous inorganic particulate of the total pore volume of grain.
The method for preparing porous inorganic particulate, the method includes：Porous inorganic particulate, the porous inorganic particulate are provided With by mercury intrusion porosimetry measure be more than 1.0cc/gm (that is, or measured by mercury intrusion porosimetry, with 0.01cc/gm be to increase The arbitrary value for being more than 1.0cc/gm and being up to and include 10.0cc/gm of amount, such as 6.00cc/gm, or with 0.01cc/gm be to increase Any range for being more than 1.0cc/gm and being up to and include the value of 10.0cc/gm of amount, for example, about 1.01cc/gm is to about Total pore volume 9.99cc/gm)；And the particle is made to be subjected to being enough to form porous, inorganic in dry solvent-free environment The mechanical force of the amount of grain, the porous inorganic particulate have by mercury intrusion porosimetry measures less than 1.0cc/gm (or with 0.01cc/ Gm is the arbitrary value for being more than 0cc/gm and being up to and include 1.0cc/gm of increment, such as 0.32cc/gm, or with 0.01cc/gm For any range for being more than 0cc/gm and being up to and include the value of 1.0cc/gm of increment, for example, about 0.30cc/gm is to about Total pore volume 0.34cc/gm), and (ii) by mercury intrusion porosimetry measure be less than 0.3cc/gm (or with 0.01cc/gm be increase The arbitrary value for being more than 0cc/gm and being up to and include 0.3cc/gm of amount, such as 0.09cc/gm, or using 0.01cc/gm as increment Be more than 0cc/gm be up to and include 0.3cc/gm value any range, for example, about 0.09cc/gm to about 0.11cc/gm) Particle internal pore volume, wherein the particle endoporus is defined as aperture and is less than or equal toHole.
According to the method described in embodiment 40, wherein there is the particle (i) to be more than by what mercury intrusion porosimetry measured 0cc/gm and total pore volume less than about 0.98cc/gm, and (ii) by mercury intrusion porosimetry measures more than 0cc/gm and being less than The particle internal pore volume of about 0.28cc/gm.
Method according to embodiment 40 or 41, wherein the particle has the pact that (i) is measured by mercury intrusion porosimetry The total pore volume of 0.15cc/gm to about 0.93cc/gm, and the about 0.05cc/gm that (ii) is measured by mercury intrusion porosimetry is to about The particle internal pore volume of 0.24cc/gm.
Method according to any one of embodiment 40 to 42, wherein the particle has (i) by mercury intrusion porosimetry The total pore volume of the about 0.25cc/gm to about 0.40cc/gm of measurement, and about 0.08cc/ that (ii) is measured by mercury intrusion porosimetry The particle internal pore volume of gm to about 0.16cc/gm.
Method according to any one of embodiment 40 to 43, wherein the particle has about 1.0 microns (μm) extremely About 100 μm (or with 0.1 μm 1.0 μm to about 100 μm for increment and include end value arbitrary value, such as 45.0 μm, or with 0.1 μ M is 1.0 μm to about 100 μm of increment and includes any range of the value of end value, for example, about 3.2 μm to about 50.1 μm) it is final Average particle size.
Method according to any one of embodiment 40 to 44, wherein the particle has about 2.0 μm to about 60 μm Final average particle size.
Method according to any one of embodiment 40 to 45, wherein the particle has about 40.0 μm to about 50.0 μm final average particle size.
The method for preparing composite particles
The method for preparing the composite particles according to any one of embodiment 9 to 38, the method includes：Tool is provided There are the initial porous inorganic particulate of certain total pore volume and at least one active constituent；And make the particle and the activity Ingredient is subjected to being enough to be formed the mechanical force of the amount of composite inorganic particle, the composite inorganic particle in dry solvent-free environment With the active constituent mechanically mixed in its hole, wherein the total pore volume of the composite inorganic particle is initial less than described The total pore volume of porous inorganic particulate.
The method for preparing composite particles, the method includes：Initial porous inorganic particulate and at least one activity are provided Ingredient, the initial porous inorganic particulate has is more than 1.0cc/gm (that is, or by mercury intrusion porosimetry by what mercury intrusion porosimetry measured It is measured, using 0.01cc/gm as the arbitrary value for being more than 1.0cc/gm and being up to and include 10.0cc/gm of increment, such as 6.00cc/gm, or using 0.01cc/gm as the arbitrary model for being more than 1.0cc/gm and being up to and include the value of 10.0cc/gm of increment Enclose, for example, about 1.01cc/gm to about 9.99cc/gm) total pore volume；And make the particle and active constituent in dry nothing It is subjected to being enough to be formed the mechanical force of compound porous inorganic particle in solvent environment, the compound porous inorganic particle has with machinery Mode mixes the active constituent in at least part in the hole of the composite particles, is surveyed by pressure mercury wherein the composite particles have What hole method measured be less than 1.0cc/gm (or using 0.01cc/gm being more than 0cc/gm up to and include 1.0cc/gm's as increment Arbitrary value, such as 0.32cc/gm, or using 0.01cc/gm as the value for being more than 0cc/gm and being up to and include 1.0cc/gm of increment Any range, for example, about 0.30cc/gm to about 0.34cc/gm) total pore volume, and (ii) measured by mercury intrusion porosimetry Less than 0.3cc/gm (or using 0.01cc/gm as increment be more than 0cc/gm be up to and include 0.3cc/gm arbitrary value, such as 0.09cc/gm, or using 0.01cc/gm as any range for being more than 0cc/gm and being up to and include the value of 0.3cc/gm of increment, For example, about 0.09cc/gm to about 0.11cc/gm) particle internal pore volume, and the wherein described particle endoporus is defined as aperture It is less than or equal toHole.
According to the method described in embodiment 48, wherein that there is (i) to be measured by mercury intrusion porosimetry is big for the composite particles In 0cc/gm and less than about the total pore volume of 0.98cc/gm, and (ii) by mercury intrusion porosimetry measures more than 0cc/gm and small In the particle internal pore volume of about 0.28cc/gm.
Method according to embodiment 48 or 49, wherein there is the composite particles (i) to be measured by mercury intrusion porosimetry About 0.15cc/gm to about 0.93cc/gm total pore volume, and the about 0.05cc/gm that (ii) is measured by mercury intrusion porosimetry is extremely The particle internal pore volume of about 0.24cc/gm.
Method according to any one of embodiment 48 to 50, wherein there is the composite particles (i) to be surveyed by pressure mercury The total pore volume for the about 0.25cc/gm to about 0.40cc/gm that hole method measures, and pact that (ii) is measured by mercury intrusion porosimetry The particle internal pore volume of 0.08cc/gm to about 0.16cc/gm.
Method according to any one of embodiment 48 to 51, wherein the composite particles have about 1.0 μm to about 100 μm (or with 0.1 μm 1.0 μm to about 100 μm for increment and include end value arbitrary value, such as 45.0 μm, or with 0.1 μm For 1.0 μm to about 100 μm of increment and include end value value any range, for example, about 3.2 μm to about 50.1 μm) it is final flat Equal granularity.
Method according to any one of embodiment 48 to 52, wherein the composite particles have about 2.0 μm to about 60 μm of final average particle size.
Method according to any one of embodiment 48 to 53, wherein the composite particles have about 40.0 μm to about 50.0 μm of final average particle size.
The method for preparing porous inorganic particulate and composite particles
Method according to any one of embodiment 47 to 54 is subjected to step and causes by described at least one wherein described Kind of active constituent generates smaller active ingredient particle, the smaller active ingredient particle have newly exposed inside activity at Divide surface, and the composite particles include inner inorganic particle surface, (ii) the new exposure via new exposure described in (i) Inside active constituent surface or both (iii) (i) and (ii) and smaller active ingredient particle described in (ii) at least part At least part of smaller inorganic particle described in (i) of contact.
Method according to any one of embodiment 39 to 55, wherein the inorganic particle has about 1.0nm to about The average pore size of 100.0nm.
Method according to any one of embodiment 39 to 56, wherein the inorganic particle has about 2.0nm to about 50.0nm average pore size.
Method according to any one of embodiment 39 to 57, wherein the inorganic particle has at least about 100m2/ G is up to 1500m2The BET granule surface areas of/g or bigger.
Method according to any one of embodiment 39 to 58, wherein the inorganic particle has about 100m2/ g is extremely About 500m2The BET granule surface areas of/g.
Method according to any one of embodiment 39 to 59, wherein the inorganic particle includes metallic particles.
Method according to any one of embodiment 39 to 60, wherein the inorganic particle includes mesoporous metal Grain.
Method according to any one of embodiment 39 to 61, wherein the inorganic particle includes silica Grain.
Method according to any one of embodiment 39 to 62, wherein the inorganic particle includes with trade nameCommercially available 244FP silica dioxide granule or with trade nameTitanium dioxide commercially available XDP Silicon particle, and it has been subjected to the reduction step in either case.
Method according to any one of embodiment 47 to 63, wherein at least one active constituent includes activity Drug ingedient (API), agricultural chemicals, food additives or any combination of them.
Method according to any one of embodiment 47 to 64, wherein at least one active constituent includes to have The active pharmaceutical ingredient (API) of crystal structure.
Method according to any one of embodiment 47 to 65, wherein at least one active constituent includes to be selected from The active pharmaceutical ingredient (API) of brufen, ezetimibe or any combination of them.
Method according to any one of embodiment 47 to 66, wherein (i) inorganic particle and (ii) are described extremely A kind of few active constituent is with about 100:1 to 1:The weight ratio of inorganic particle and at least one active constituent in 100 ranges In the presence of.
Method according to any one of embodiment 47 to 67, wherein (i) inorganic particle and (ii) are described extremely A kind of few active constituent is with about 10:1 to 1:The weight ratio of inorganic particle and at least one active constituent in 10 ranges is deposited .
Method according to any one of embodiment 47 to 68, wherein (i) inorganic particle and (ii) are described extremely A kind of few active constituent is with about 2:1 to 1:The weight ratio of inorganic particle and at least one active constituent in 2 ranges exists.
Method according to any one of embodiment 39 to 69, wherein the step that is subjected to is including the use of abrading-ball, spray Jet body or at least one extruder screw make the average particle size of the mixture of particle reduce.
Method according to any one of embodiment 39 to 70, wherein the step that is subjected to is including the use of abrading-ball, spray Jet body or at least one extruder screw make the particle reunite and be formed again.
A method according to any one of embodiment 39 to 71, wherein the step that is subjected to makes including the use of abrading-ball The average particle size of the mixture of grain reduces.
Method according to any one of embodiment 39 to 72 is subjected to step and makes institute including the use of abrading-ball wherein described Particle is stated to reunite and formed again.
Method according to any one of embodiment 39 to 73, wherein described be subjected to step including grinding chamber and mill Occur in the vibrator of ball.
According to the method described in embodiment 74, wherein the vibrator at about 12 hertz (Hz) to about 90 hertz (Hz) (or using 1.0Hz as the arbitrary value of the 12Hz of increment to 90Hz, such as 18Hz, or using 1.0Hz as the 12Hz of increment in range To any range of the value of 90Hz, for example, about 18Hz to about 28Hz) frequency under operate.It is desirable that vibrator is being permitted Perhaps crystalline active ingredient (such as drug) undergoes when in composite particles form and is carried out under the frequency that amorphization is amorphous state Operation.In some desired embodiments, for example, the range of the frequency of the induction amorphization is according to active constituent used About 18Hz to about 30Hz.See, for example, the sample 5 and 11 in Examples below 1-2, the wherein frequency of 20Hz leads to crystalline drug Brufen and ezetimibe amorphization are amorphous state.
Method according to embodiment 74 or 75, wherein the vibrator operates grinding in less than about 25 minutes Time is (or with 1.0 seconds greater than about 10 seconds arbitrary values for increment, such as 45 seconds, or with 1.0 seconds about 10 seconds to 25 for increment Any range of the value of minute, for example, about 60 seconds to about 5 minutes).It is desirable that vibrator operation milling time (and Frequency) allow crystalline active ingredient (such as drug) to undergo amorphization when in composite particles form for amorphous state.One In a little desired embodiments, for example, the range of the milling time of the induction amorphization is about 1.0 according to active constituent used Minute was to about 20 minutes.See, for example, the sample 5 and 11 in Examples below 1-2, wherein when grinding in 1.0 minutes and 5 minutes Between cause crystalline drug brufen and ezetimibe amorphization to be amorphous state respectively.
Method according to any one of embodiment 39 to 76, wherein described be subjected to step including grinding chamber and mill Occur in the vibrator of ball, under frequency of the vibrator in about 20 hertz (Hz) to about 90 hertz of (Hz) ranges The milling time of operation less than about 25 minutes.In some desired embodiments, by vibrator in about 20Hz to about About 1.0 minutes to about 5 minutes milling times are operated under frequency within the scope of 30Hz.
Method according to any one of embodiment 39 to 77, wherein described be subjected to step including grinding chamber and mill Occur in the vibrator of ball, under frequency of the vibrator in about 20 hertz (Hz) to about 40 hertz of (Hz) ranges The milling time of operation less than about 90 seconds.
Method according to any one of embodiment 39 to 78, wherein described be subjected to step including grinding chamber and mill Occur in the vibrator of ball, under frequency of the vibrator in about 20 hertz (Hz) to about 30 hertz of (Hz) ranges The milling time of operation less than about 60 seconds.
Method according to any one of embodiment 47 to 79, wherein the method further include：By the inorganic particulate Grain and at least one active constituent are introduced into the vibrator including grinding chamber and abrading-ball, and the vibrator is about It is operated under frequency in 20 hertz (Hz) to about 90 hertz of (Hz) ranges.
Method according to any one of embodiment 70 to 80, wherein described (i) inorganic particle, (ii) at least one Active constituent and (iii) abrading-ball are with about 1 to 100:1 to 100:The weight ratio of (i) and (ii) and (iii) in 1 to 100 range are deposited .
Method according to any one of embodiment 70 to 81, wherein described (i) inorganic particle, (ii) at least one Active constituent and (iii) abrading-ball are with about 1 to 10:1 to 10:The weight ratio of (i) and (ii) and (iii) in 1 to 10 range exists.
Method according to any one of embodiment 39 to 69, wherein the step that is subjected to is including the use of injection fluid The average particle size of the mixture of particle is set to reduce.
According to the method described in any one of embodiment 39 to 69 and 83, wherein described be subjected to step including the use of injection Fluid makes the particle reunite and be formed again.
Method according to any one of embodiment 39 to 69 and 83 to 84 is subjected to step and is ground in injection wherein described Occur in mill apparatus.
Method according to any one of embodiment 39 to 69, wherein described be subjected to step including the use of at least one Extruder screw makes the average particle size of the mixture of particle reduce.
According to the method described in any one of embodiment 39 to 69 and 86, wherein described be subjected to step including the use of at least One extruder screw makes the particle reunite and be formed again.
Method according to any one of embodiment 39 to 69 and 86 to 87, wherein described be subjected to step in extruder Middle generation.
Method according to any one of embodiment 47 to 88, wherein the method further include：It is walked in the reduction Before rapid, dry (i) described inorganic particle, (ii) described at least one active constituent or (iii) (i) and (ii) the two.
Method according to any one of embodiment 39 to 89, wherein the mixture of the particle includes based on described The total weight of the mixture of the particle less than about water of 5.0 weight %.
Method according to any one of embodiment 39 to 90, wherein the mixture of the particle includes based on described The total weight of the mixture of the particle less than about water of 1.0 weight %.
Method according to any one of embodiment 39 to 91, wherein the method less than about 10 minutes (or with 1.0 seconds greater than about 10 seconds to 10 minutes random times for increment) in reach grain equilibrium, the grain equilibrium is indicated into one Step processing does not lead to point when larger particles.Desirably, grain equilibrium is also represented by the crystalline active ingredient in composite particles and occurs Amorphization is the point of amorphous state.
Method according to any one of embodiment 39 to 92, wherein by the method generate the particle most Whole average particle size is more than the initial average particle size.
Method according to any one of embodiment 39 to 93, wherein described in the final average particle size ratio of the particle Initial average particle size greatly at least 1.0%.
Method according to any one of embodiment 39 to 94, wherein described in the final average particle size ratio of the particle Initial average particle size about 5.0% to about 25.0%.
Method according to any one of embodiment 47 to 95, wherein the finally average compound grain of the composite particles The initial average particle size greatly at least 1.0% of the degree inorganic particle more described than (i) or (ii) described at least one active constituent.
Method according to any one of embodiment 47 to 96, wherein the finally average compound grain of the composite particles The initial average particle size about 5.0% of the degree inorganic particle more described than (i) or (ii) described at least one active constituent is to about 25.0%.
Porous inorganic particulate, composite particles and pharmaceutical composition
The porous inorganic particulate formed by the method according to any one of embodiment 39 to 97.
The composite particles formed by the method according to any one of embodiment 47 to 97.
A kind of pharmaceutical composition, including the composite particles according to any one of embodiment 9 to 38.
According to the pharmaceutical composition described in embodiment 100, in the form of selected from pill, tablet and capsule.
The purposes of porous inorganic particulate and composite particles
By the particle of the method formation according to any one of embodiment 39 to 97 or according to embodiment 1 to 38 It is used as by institute with the particle described in any one of 98 to 99 or the pharmaceutical composition according to embodiment 100 or 101 State the purposes of the reagent at least one active delivery to environment.
Particle is as by the purposes of the reagent at least one active delivery to environment, the particle to include more Hole inorganic particle, the porous inorganic particulate have (i) by mercury intrusion porosimetry measures less than 1.0cc/gm (or with 0.01cc/ Gm is the arbitrary value for being more than 0cc/gm and being up to and include 1.0cc/gm of increment, such as 0.32cc/gm, or with 0.01cc/gm For any range for being more than 0cc/gm and being up to and include the value of 1.0cc/gm of increment, for example, about 0.30cc/gm is to about Total pore volume 0.34cc/gm), and (ii) by mercury intrusion porosimetry measure be less than 0.3cc/gm (or with 0.01cc/gm be increase The arbitrary value for being more than 0cc/gm and being up to and include 0.3cc/gm of amount, such as 0.09cc/gm, or using 0.01cc/gm as increment Be more than 0cc/gm be up to and include 0.3cc/gm value any range, for example, about 0.09cc/gm to about 0.11cc/gm) Particle internal pore volume, wherein the particle endoporus is defined as aperture and is less than or equal toHole.
The purposes of particle according to embodiment 103, wherein there is the particle (i) to be measured by mercury intrusion porosimetry Total pore volume more than 0cc/gm and less than about 0.98cc/gm, and (ii) by mercury intrusion porosimetry measures more than 0cc/gm and Particle internal pore volume less than about 0.28cc/gm.
The purposes of particle according to embodiment 103 or 104, wherein the particle has (i) by mercury intrusion porosimetry The total pore volume of the about 0.15cc/gm to about 0.93cc/gm of measurement, and about 0.05cc/ that (ii) is measured by mercury intrusion porosimetry The particle internal pore volume of gm to about 0.24cc/gm.
The purposes of particle according to any one of embodiment 103 to 105, wherein the particle has (i) by pressing The total pore volume for the about 0.25cc/gm to about 0.40cc/gm that mercury gaging hole method measures, and pact that (ii) is measured by mercury intrusion porosimetry The particle internal pore volume of 0.08cc/gm to about 0.16cc/gm.
The purposes of particle according to any one of embodiment 103 to 106, wherein the particle has about 1.0 μm To about 100 μm (or with 0.1 μm 1.0 μm to about 100 μm for increment and include end value arbitrary value, such as 45.0 μm, or with 0.1 μm for 1.0 μm to about 100 μm of increment and include end value value any range, for example, about 3.2 μm to about 50.1 μm) Average particle size.
The purposes of particle according to any one of embodiment 103 to 107, wherein the particle has about 2.0 μm To about 60 μm of average particle size.
The purposes of particle according to any one of embodiment 103 to 108, wherein the particle has about 40.0 μm To about 50.0 μm of average particle size.
The purposes of particle according to any one of embodiment 103 to 109, wherein the particle includes to have on it There is the inorganic particle of newly exposed inner inorganic particle surface mechanically changed.
Composite particles are as by the purposes of the reagent at least one active delivery to environment, described compound Grain include：(i) inorganic particle, and (ii) mechanically mix at least one of hole activity of inorganic oxide particles at Point, wherein the composite particles have (i) by mercury intrusion porosimetry measures less than 1.0cc/gm (or using 0.01cc/gm as increment The arbitrary value for being more than 0cc/gm and being up to and include 1.0cc/gm, such as 0.32cc/gm, or using 0.01cc/gm as increment Any range of the value of 1.0cc/gm, for example, about 0.30cc/gm to about 0.34cc/gm are up to and included more than 0cc/gm) Total pore volume, and (ii) by mercury intrusion porosimetry measure be less than 0.3cc/gm (or using 0.01cc/gm be increment be more than 0cc/ Gm is up to and includes the arbitrary value of 0.3cc/gm, such as 0.09cc/gm, or is more than 0cc/gm using 0.01cc/gm as increment Up to and include 0.3cc/gm value any range, for example, about 0.09cc/gm to about 0.11cc/gm) particle in hole body Product, wherein the particle endoporus is defined as aperture and is less than or equal toHole.
The purposes of composite particles according to embodiment 111, wherein the composite particles have (i) by pressure mercury gaging hole The total pore volume for being more than 0cc/gm and being less than about 0.98cc/gm that method measures, and (ii) are more than by what mercury intrusion porosimetry measured 0cc/gm and the particle internal pore volume for being less than about 0.28cc/gm.
The purposes of composite particles according to embodiment 111 or 112, wherein the composite particles have (i) by pressing The total pore volume for the about 0.15cc/gm to about 0.93cc/gm that mercury gaging hole method measures, and pact that (ii) is measured by mercury intrusion porosimetry The particle internal pore volume of 0.05cc/gm to about 0.24cc/gm.
The purposes of composite particles according to any one of embodiment 111 to 113, wherein the composite particles have (i) total pore volume of the about 0.25cc/gm to about 0.40cc/gm measured by mercury intrusion porosimetry, and (ii) by mercury intrusion porosimetry The particle internal pore volume of the about 0.08cc/gm to about 0.16cc/gm of measurement.
The purposes of composite particles according to any one of embodiment 111 to 114, wherein the composite particles have About 1.0 μm to about 100 μm (or with 0.1 μm 1.0 μm to about 100 μm for increment and include end value arbitrary value, such as 45.0 μ M, or with 0.1 μm 1.0 μm to about 100 μm for increment and include end value value any range, for example, about 3.2 μm to about 50.1 μm) average particle size.
The purposes of composite particles according to any one of embodiment 111 to 115, wherein the composite particles have About 2.0 μm to about 60 μm of average particle size.
The purposes of composite particles according to any one of embodiment 111 to 116, wherein the composite particles have About 40.0 μm to about 50.0 μm of average particle size.
The purposes of composite particles according to any one of embodiment 111 to 117, wherein the porous, inorganic aoxidizes Composition granule includes the inner inorganic particle surface newly exposed, and (ii) described at least one active constituent and the new exposure Inner inorganic particle surface contacts.
The purposes of composite particles according to any one of embodiment 111 to 118, wherein at least one activity Ingredient includes the inside active constituent surface newly exposed, and at least one active constituent is via new exposure described in (i) Both inner inorganic particle surface, the inside active constituent surface of (ii) described new exposure or (iii) (i) and (ii) with it is described Inorganic particle contacts.
The purposes of particle according to any one of embodiment 103 to 110 or according in embodiment 111 to 119 The purposes of any one of them composite particles, wherein the inorganic particle has the average pore size of about 1.0nm to about 100.0nm.
The purposes of particle according to any one of embodiment 103 to 110 or according in embodiment 111 to 120 The purposes of any one of them composite particles, wherein the inorganic particle has the average pore size of about 2.0nm to about 50.0nm.
The purposes of particle according to any one of embodiment 103 to 110 or according in embodiment 111 to 121 The purposes of any one of them composite particles, wherein the inorganic particle has at least about 100m2/ g is up to 1500m2/ g or The BET granule surface areas of bigger.
The purposes of particle according to any one of embodiment 103 to 110 or according in embodiment 111 to 122 The purposes of any one of them composite particles, wherein the inorganic particle has about 100m2/ g to about 400m2/ g or bigger BET granule surface areas.
The purposes of particle according to any one of embodiment 103 to 110 or according in embodiment 111 to 123 The purposes of any one of them composite particles, wherein the inorganic particle includes inorganic oxide particles.
The purposes of particle according to any one of embodiment 103 to 110 or according in embodiment 111 to 124 The purposes of any one of them composite particles, wherein the inorganic oxide particles include metal oxide particle.In a reality It applies in scheme, metal oxide particle is mesoporous metal oxide particle.
The purposes of particle according to any one of embodiment 103 to 110 or according in embodiment 111 to 125 The purposes of any one of them composite particles, wherein the inorganic particle includes silica dioxide granule.
The purposes of particle according to any one of embodiment 103 to 110 or according in embodiment 111 to 126 The purposes of any one of them composite particles, wherein the inorganic particle includes with trade nameIt is obtained commercially available from 244FP Silica dioxide granule or with trade nameSilica dioxide granule commercially available XDP, the silica Grain has been prepared via the method according to any one of embodiment 39 to 97 in either case.
The purposes of composite particles according to any one of embodiment 111 to 127, wherein (i) inorganic particle (ii) described at least one active constituent is with about 100:1 to 1:Inorganic particle in 100 ranges and at least one activity The weight ratio of ingredient exists.
The purposes of composite particles according to any one of embodiment 111 to 128, wherein (i) inorganic particle (ii) described at least one active constituent is with about 10:1 to 1:Inorganic particle in 10 ranges and at least one activity at The weight ratio divided exists.
The purposes of composite particles according to any one of embodiment 111 to 129, wherein (i) inorganic particle (ii) described at least one active constituent is with about 2:1 to 1:Inorganic particle in 2 ranges and at least one active constituent Weight ratio exist.
The purposes of composite particles according to any one of embodiment 111 to 130, wherein the composite particles include Total weight based on the composite particles less than about water of 5.0 weight %.
The purposes of composite particles according to any one of embodiment 111 to 131, wherein the composite particles include Total weight based on the composite particles less than about water of 1.0 weight %.
The purposes of composite particles according to any one of embodiment 111 to 132, wherein the composite particles are basic On be made of the inorganic particle and at least one active constituent.
The purposes of composite particles according to any one of embodiment 111 to 133, wherein the composite particles are by institute State inorganic particle and at least one active constituent composition.
The purposes of composite particles according to any one of embodiment 111 to 134, wherein at least one activity Ingredient includes active pharmaceutical ingredient (API).
The purposes of composite particles according to any one of embodiment 111 to 135, wherein at least one activity Ingredient includes the active pharmaceutical ingredient (API) with tial crystalline structure.
The purposes of composite particles according to any one of embodiment 111 to 136, wherein at least one activity Ingredient includes the active pharmaceutical ingredient (API) selected from brufen, ezetimibe or any combination of them.
Particle according to any one of embodiment 103 to 110 or according to any one of embodiment 111 to 133 Purposes of the composite particles as dental product or oral care product.
Particle according to any one of embodiment 103 to 110 or according to any one of embodiment 111 to 133 Purposes of the composite particles as skin-protection product.
Particle according to any one of embodiment 103 to 110 or according to any one of embodiment 111 to 133 Purposes of the composite particles as cosmetic product.
Particle according to any one of embodiment 103 to 110 or according to any one of embodiment 111 to 133 The composite particles provide the purposes of product as nutrition.
The purposes of composite particles according to any one of embodiment 102 to 141, wherein the environment includes suffering from Person.
The purposes of composite particles according to any one of embodiment 102 to 142, wherein the environment includes patient Enteron aisle.
The purposes of composite particles according to any one of embodiment 111 to 133, wherein at least one activity Ingredient includes plant nutrient or insecticide.
The purposes of composite particles according to any one of embodiment 102 to 133 and 144, wherein the environment packet It includes near plant or plant.
Particle according to any one of embodiment 103 to 110 or according to any one of embodiment 111 to 133 Purposes of the composite particles in catalyst application.
The purposes of particle according to any one of embodiment 102 to 110 or according to embodiment 111 to 133 and The purposes of composite particles described in any one of 146, wherein the environment includes process reactor.
The purposes of particle according to any one of embodiment 102 to 147, wherein the environment includes containing water ring Border.
The purposes of composite particles according to any one of embodiment 111 to 148, wherein the composite particles make to At least one active constituent of few 50 weight % can be dissolved in the environment in 20 minutes.
The purposes of composite particles according to any one of embodiment 111 to 149, wherein the composite particles make to At least one active constituent of few 50 weight % can be in 5 minutes dissolved in the environment.
It will be appreciated that though above-mentioned porous inorganic particulate, composite particles, method and purposes be described as " comprising " one or Multiple components or step, but above-mentioned porous inorganic particulate, composite particles, method and purposes also can " comprising " porous inorganic particulate, Any of above component or step of composite particles, method and purposes, " being made from it " or " consisting essentially of ".Therefore, exist In the case of describing the present invention or part of it using open term such as " comprising ", it should be readily appreciated that (unless in addition Indicate) present invention or part thereof of description also should be interpreted that using term "consisting essentially of ..." as described below or " Consists of " or its variations describe the present invention or part of it.
As used herein, term "comprising", " comprising ", " having ", " containing ", " it is characterized in that " or they it is any its What its modification was intended to cover nonexcludability includes the component, and limitation is clearly dictated otherwise by any.For example, " comprising " is wanted Porous inorganic particulate, the composite particles of plain list (for example, component or step), method and/or purposes might not be only limitted to that A little elements (or component or step), but may also comprise not expressly listed or porous inorganic particulate, composite particles, method and/or use Way intrinsic other elements (or component or step).
As used herein, transition phrase " Consists of " and " by ... constitutes " the unspecified any element of exclusion, step or Component.For example, " Consists of " used in claim or " by ... constitute " make claim be limited to have in claim Component, material or the step that body refers to, in addition to usual impurity (that is, impurity in given component) associated there.When short Language " Consists of " or " by ... constitute " appear in the clause of claim, rather than when following closely after preamble, phrase " by ... Composition " or " by ... constitute " only it is limited in element described in the clause (or component or step)；And other elements (or component) It is not excluded except claim as a whole.
As used herein, transition phrase "consisting essentially of ..." and " substantially by ... constitutes " include except word for defining The porous inorganic particulate of material, step, feature, component or element on face except those disclosed, composite particles, method and/ Or purposes, precondition are that these additional materials, step, feature, component or element do not substantially affect hair claimed Bright fundamental characteristics and novel features.Term "consisting essentially of ..." is in the centre between " comprising " and " Consists of " Area.
In addition, it should be understood that porous inorganic particulate as described herein, composite particles, method and/or purposes may include it is any It is component and feature as described herein, consisting essentially of or be made from it, it (shows or does not show in attached drawing as shown in the drawing Any feature).In other words, in some embodiments, porous inorganic particulate of the invention, composite particles, method and/or use Way does not have any supplementary features in addition to those shown in attached drawing, and such supplementary features are not illustrated in attached drawing, It is particularly excluded except porous inorganic particulate, composite particles, method and/or purposes.In other embodiments, of the invention Porous inorganic particulate, composite particles, method and/or purposes there are one or more supplementary features not shown in figures.
Following examples further illustrate the present invention, these embodiments are not construed in any way to the scope of the invention Limit.On the contrary, be clearly understood that, can by means of various other embodiments, modification and they be equal Object, after the narration for reading this paper, under the premise of not departing from the spirit and/or scope of the appended claims of the present invention, Themselves can be associated by those skilled in the art.
Embodiment
Following embodiment describes the method that (i) is used to prepare porous inorganic particulate and composite particles according to the present invention, and (ii) assessment in drug course of dissolution to porous inorganic particulate and composite particles.
In embodiment, following silica grades shown in table 1 are utilized.
Table 1：Silica used in embodiment
For silica shown in table 1, Malvern MASTERSIZER are usedTM2000 (are purchased from Malvern Instrument Ltd.) pass through laser light scattering (according to ASTM B822-10) measurement median particle.Granularity is defined as volume point The median particle of cloth.BET surface area is analyzed available from the nitrogen adsorption described in document.Mean pore sizes, pore volume and aperture point Cloth is pressed into based on mercury injection methodIt is calculated in the hole of size.Pore volume is defined as the accumulation within the scope of same apertures Pore volume, and mean pore sizes be measured as 50% pore volume contributed by more aperture and 50% pore volume by more macropore institute The aperture (size) of contribution.
Fig. 1 shows silica dioxide granule (used in such as embodiment of the present invention244FP andXDP3050 silica) surface group, interacted therewith for active constituent.
Fig. 2A -2D are shown244FP silica is since grinding is (that is, using described in Examples below 1 Exemplary vibrations ball mill) variation.Fig. 2A (that is, upper left side photo) is shown244FP silica is being ground Photo before.Fig. 2 B (that is, upper right side photo) are shownThe photo of 244FP silica after milling.Such as Shown in Fig. 2 C-2D, process of lapping significantly reducesThe accumulation pore volume of 244FP silica.Referring to Fig. 2 C (that is, lower left photo)244FP silica accumulation pore volume before the grinding and Fig. 2 D are (that is, right Lower section photo)The accumulation pore volume of 244FP silica after milling, is such as measured by mercury injection method.
Similar result is illustrated in Fig. 3 A-3D, and Fig. 3 A-3D are shownXDP3050 silica is due to grinding The variation of mill.Fig. 3 A (that is, upper left side photo) are shownThe photo of XDP3050 silica before the grinding.Figure 3B (that is, upper right side photo) is shownThe photo of XDP3050 silica after milling.Such as Fig. 3 C-3D institutes Show, process of lapping significantly reducesThe accumulation pore volume of XDP3050 silica.Referring to Fig. 3 C (that is, lower-left Square photo)XDP3050 silica accumulation pore volume before the grinding and Fig. 3 D are (that is, lower right Photo)The accumulation pore volume of XDP3050 silica after milling, is such as measured by mercury injection method.
Embodiment 1：Include the formation of the composite particles of silica and brufen (IBU)
By by the silica dioxide granule of following amount and brufen (IBU) introducing vibrator (as shown in Table 2 below) In MixerMillMM400 (can be commercially available from RetschGmbH＆Co. (Haan, Germany)), composite particles are prepared.Vibration Ball mill is made up of：(i) stainless-steel grinding room and two (2) stainless steel balls of the building volume for 25 milliliters (ml), each It is weighed as 7.0 grams (g) and a diameter of 12 millimeters (mm).
Silica sample is used as former state by what is provided.Each silica sample is added in vibratory chamber.
Brufen with about 2-3mm initial median granularities is added in vibratory chamber.
Vibrating mill is set in given frequency and runs milling time as shown in table 3 below.
After being co-mulled and made into, pipettes each sample from vibratory chamber and analyzed.Figure 10 and Figure 11 is shown and shape in embodiment 1 At those of similar composite particles (amplification factor 1000) photo, that is, include (1)244FP silica With brufen (Figure 10), and (2)The composite particles of XDP3050 silica and brufen (Figure 11).
Test of many times is implemented using each milling time changed from 1 minute (min) to 25min.In addition, being answered what is be co-mulled and made into Close tabletted dose together of particle and other compression aids (such as polyethylene glycol (PEG), NaLS (SLS) etc.) Type.
The amorphization for the IBU being co-mulled and made into is confirmed by DSC and X-RD researchs.By and using USP dissolvers II and The medium (for example, acetate buffer) of pH 4.5 carries out drug release studies.
It is believed that during being co-mulled and made into,Hydrogen bond between the silanol group of silica and the functional group of IBU Formation is the key that drug amorphization.In order to confirm IBU amorphizations, X-ray diffraction studies (XRD) are carried out.Such as Fig. 4 institutes Show,3050 silica of XDP and244FP silica is each contributed to via being co-mulled and made into process Reduce the crystallinity of IBU.However, the IBU individually ground does not lead to amorphous form.This showsSilica Effect in being amorphous state by crystalline drug amorphization via the process that is co-mulled and made into.
In addition, carry out DSC research with understand amorphization andBetween the silanol group and IBU of silica Possibility interaction.DSC heat score-curves shown in Fig. 5 A- Fig. 5 B confirm the variation of enthalpy and peak shape symmetry simultaneously. The variation of peak symmetry has strongly suggested that silanol group and the interaction of IBU.The variation of enthalpy is also shown that IBU from crystal knot Structure is converted into amorphous form.
In addition, as shown in fig. 6, under various milling times with3050 silica of XDP is co-mulled and made into The X ray diffracting data of the combination of brufen indicates that composite particles group subassembly is from crystalline state (that is, such as along given curve figure Sharp peak indicated by, for example, corresponding to 10 seconds experiment curve graph) be converted into amorphous state (that is, such as along given curve figure Indicated by smoother curve graph with less sharp peak, such as corresponding to the curve graph of experiment in 60 seconds).
Make to be co-mulled and made into sample in 4.5 buffer solutions of pHXDP 3050+IBU and244FP Silica+IBU is dissolved, and is compared with the dissolving of the IBU individually ground, as shown in Figure 7.It is buffered in pH4.5 Milling time pair is measured in liquidXDP3050+IBU and244FP silica+IBU's grinds altogether The influence of grind away product dissolving, and be compared again with the dissolving of the IBU individually ground, as shown in Figure 9.Acquired results show Go out, compared to the IBU individually ground, the dissolving for being co-mulled and made into sample significantly improves.It is believed that shape during being co-mulled and made into At IBU amorphous form, dissolve improved variation.This shows the biology that can improve crystalline drug using this method Utilization rate.
It is also observed, under the various press powers of 15KN to 25KN,Hydrogen bond between silica and IBU It remains unchanged, as shown in the solubility curve of the tablet by being suppressed under these power in Fig. 8.
Figure 12 shows that milling time includes with 1 to use the regulation summarized such as embodiment 1:1 weight ratio or 1:5 weights Amount than withThe influence of the tablet dissolved of the composite particles for the brufen that 3050 silica of XDP is co-mulled and made into.Such as It is as discussed above to prepare sample C3 (IBU not ground), C1 (IBU individually ground), 3 (being co-mulled and made into 5min), 1 (be co-mulled and made into 15min), 4 (being co-mulled and made into 25min) and 5 (being co-mulled and made into 1min).As shown in figure 12, compared to other samples, sample 5 is (at 20Hz It is co-mulled and made into 1min) excellent drug dissolving is provided.
Figure 13 show milling time to use the regulation summarized such as example 1 above comprising with various weight ratios withThe influence of the tablet dissolved of the composite particles for the brufen that 3050 silica of XDP is co-mulled and made into.Such as institute above Discussion prepares sample C3 (IBU not ground), C4 (grinding IBU 1min), C5 (grinding IBU 40min), 6 (is co-mulled and made into 60min), 7 (being co-mulled and made into 40min) and 5 (being co-mulled and made into 1min).As shown in figure 13, compared to other samples, sample 5 is (at 20Hz It is co-mulled and made into 1min) excellent drug dissolving is provided.
Figure 14 shows given carrier and storage time to using the rule being similar to as summarized in example 1 above The influence of the tablet dissolved of the composite particles comprising the brufen being co-mulled and made into various carriers of journey.As shown in figure 14, compared to Other samples, including as carrierThe sample of XDP silica is (that is, comprising combining with brufenThe composite particles of XDP silica) it is special even if still providing excellent drug dissolving after one week storage time Property.Although PVPK30- brufen composite particles have been initially provided of good drug dissolution characteristics, drug dissolution characteristics are storing It is significantly reduced after one week.
To sum up, in this embodiment, from from the XRD and DSC that obtain, be identified through withDioxy SiClx is co-mulled and made into, and drug starts from crystal transformation to be amorphous form.The silanol of the highly dense of silica Base interacts with crystalline drug under mechanical force, forms amorphous form.Interaction DSC heat score-curves (Fig. 5 A- figures 5B) confirmed with X ray diffracting data (Fig. 6).Relative to drug is not ground, the dissolving of the drug individually ground does not show that Any improvement；However, withThe IBU that silica is co-mulled and made into shows that dissolving significantly improves.This is confirmed, is crystallized Drug withSilica, which is co-mulled and made into, helps to create stable amorphous form, this can help to improve drug Bioavailability.This method is not related to solvent or any special installation, thus sounds and improve crystalline drug and poor water-soluble Property drug oral bioavailability rate it is industrial viable, save cost and time saving method.
Embodiment 2：Include the formation of the composite particles of silica and ezetimibe
Using the regulation and material preparation composite particles described in above example 1, unlike using ezetimibe and Non- brufen (IBU).Use composite particles composition component as shown in table 4 below.
Ezetimibe with about 2mm-3mm initial median granularities is added in vibratory chamber.
Vibrating mill is set in given frequency and runs milling time as shown in table 5 below.
Table 4：Composite particles form
Table 5：Technological parameter
After being co-mulled and made into, pipettes each sample from vibratory chamber and analyzed.Figure 15 and Figure 16 show with shape in embodiment 2 At those of similar composite particles (amplification factor 1000) photo, that is, include (1)XDP silica With ezetimibe (sample 12, Figure 15), and (2)3050 silica of XDP and ezetimibe (sample 11, Figure 16) composite particles.
As shown in figure 17, under various milling times withThe ezetimibe that XDP silica is co-mulled and made into Combination X ray diffracting data instruction, composite particles group subassembly is from crystalline state (that is, such as along the sharp of given curve figure Indicated by peak, for example, corresponding to the curve graph of experiment in 5 minutes) amorphous state is converted into (that is, such as having along given curve figure Less indicated by the smoother curve graph of sharp peak, such as corresponding to the curve graph of experiment in 50 minutes).
Figure 18 show (i) individually ezetimibe compared to (ii) withXDP silica is ground altogether The dissolving of the ezetimibe (as described in example 2 above) of mill.Sample C9 is shown in FIG. 18 (in water with mortar and pestle Be co-mulled and made into 15min), C10 (EZB not ground in water), 11 (being co-mulled and made into 5min), 12 (being co-mulled and made into 20min), 13 (be co-mulled and made into 50min) and C11 (15min is co-mulled and made into HCl with mortar and pestle).As shown in figure 18, composite particles of the invention are (that is, sample Product 11) with regard to drug dissolving for be better than all the remaining samples.
To sum up, show that factor including but not limited to below influences the medicine of gained composite particles in this embodiment Object dissolves：Drug carrying capacity, frequency used, milling time used and the solvent and solvent-free system of composite particles.It is believed that being used for Forming the parameter of sample 11 leads to crystalline drug amorphization during be co-mulled and made into, and different technological parameter (such as sample Used in 12-13) do not result in crystalline drug amorphization.
Embodiment 3：Include the formation of the composite particles of silica and brufen
Use regulation described in embodiment 1 and material preparation composite particles.It is combined using composite particles as shown in table 6 below Object component.
Brufen is added in vibratory chamber.
Vibrating mill is set in given frequency and runs milling time as shown in table 7 below.
Each sample is assessed for following item：(i) total pore volume measured by mercury intrusion porosimetry, and (ii) The particle internal pore volume measured by mercury intrusion porosimetry, wherein particle endoporus are defined as aperture and are less than or equal toHole. As a result it is shown in the following table 8.
Table 8：Total pore volume and particle internal pore volume
Sample Total pore volume (ml/g) Particle internal pore volume (ml/g) Grain equilibrium
C12 5.94 1.7 -
14 0.76 0.16 It is
15 0.92 0.20 It is
16 0.34 0.09 It is
17 0.76 0.20 It is
18 1.16 0.30 It is no
C13 2.14 1.63 -
19 0.76 0.21 It is
20 0.93 0.19 It is
21 0.30 0.11 It is
22 0.69 0.24 It is
23 0.82 0.17 It is
24 1.27 0.48 It is no
Figure 19 A- Figure 19 B show display(i.e. Figure 19 A) and the grinding before the grinding of 244FP silica The curve graph of the accumulation pore volume of (i.e. Figure 19 B, the sample 17 of embodiment 3) later.
Although using a limited number of embodiment, invention has been described, these specific embodiments are not purport It is described herein as the range with the claimed invention in limitation.When consulting the exemplary implementation scheme of this paper, for this It may be it is readily apparent that further modification form, equivalent form and variations be for the those of ordinary skill in field It is possible.Unless otherwise specified, all parts and percentages in embodiment and in the rest part of specification are all with weight Meter.In addition, specification or any numberical range as described in the claims such as representation property, units of measurement, condition, physics State or the numberical range of percentage specifically gathered are intended to through reference or other modes clear literally meaning herein Include the subset of any numerical value in any range including falling any numerical value in this kind of range.For example, whenever public affairs Lower limit R is issuedLWith upper limit RUNumberical range when, all specifically disclose any numerical value R fallen within the scope of this.Specifically, have Body discloses following number R in the range：R=RL+k(RU-RL), wherein k is the variable in 1% to 100% range, is increased Amount is 1%, such as k is 1%, 2%, 3%, 4%, 5%；... 50%, 51%, 52%；... 95%, 96%, 97%, 98%, 99% or 100%.In addition, it is also specifically disclosed that such as any numberical range indicated with any two R values calculated above.Ability The technical staff in domain is as described above with attached drawing it will be apparent that in addition to the present invention's shown and described herein other than those Any modification.Such modification is intended to fall in the scope of the appended claims.Herein cited all publications It is incorporated by reference and is incorporated herein.

Claims (152)

1. porous inorganic particulate, it is total less than 1.0cc/gm that there is the porous inorganic particulate (i) to be measured by mercury intrusion porosimetry Pore volume, and the particle internal pore volume less than 0.3cc/gm that (ii) is measured by mercury intrusion porosimetry, wherein the particle endoporus It is defined as aperture to be less than or equal toHole.
2. porous inorganic particulate according to claim 1, wherein that there is (i) to be measured by mercury intrusion porosimetry is big for the particle In 0cc/gm and less than about the total pore volume of 0.98cc/gm, and (ii) by mercury intrusion porosimetry measures more than 0cc/gm and small In the particle internal pore volume of about 0.28cc/gm.
3. porous inorganic particulate according to claim 1 or 2, wherein there is the particle (i) to be measured by mercury intrusion porosimetry About 0.15cc/gm to about 0.93cc/gm total pore volume, and the about 0.05cc/gm that (ii) is measured by mercury intrusion porosimetry is extremely The particle internal pore volume of about 0.24cc/gm.
4. porous inorganic particulate according to any one of claim 1 to 3, wherein there is the particle (i) to be surveyed by pressure mercury The total pore volume for the about 0.25cc/gm to about 0.40cc/gm that hole method measures, and pact that (ii) is measured by mercury intrusion porosimetry The particle internal pore volume of 0.08cc/gm to about 0.16cc/gm.
5. porous inorganic particulate according to any one of claim 1 to 4, wherein the particle has about 1.0 microns of (μ M) to about 100 μm of average particle size.
6. porous inorganic particulate according to any one of claim 1 to 5, wherein the particle have about 2.0 μm to about 60 μm of average particle size.
7. porous inorganic particulate according to any one of claim 1 to 6, wherein the particle have about 30.0 μm to about 50.0 μm of average particle size.
8. porous inorganic particulate according to any one of claim 1 to 7, wherein the particle includes to have on it newly The aggregate for the inorganic particle of exposed inner inorganic particle surface mechanically changed.
9. composite particles, the composite particles include porous inorganic particulate according to any one of claim 1 to 8 and with Mechanical system mixes at least one of the hole of inorganic particle active constituent, wherein the composite particles have (i) by pressing The total pore volume less than 1.0cc/gm that mercury gaging hole method measures, and (ii) are less than 0.3cc/gm's by what mercury intrusion porosimetry measured Particle internal pore volume.
10. composite particles, the composite particles include porous inorganic particulate and mechanically mix the hole of the inorganic particle At least one of active constituent, wherein there is the composite particles (i) to be less than 1.0cc/gm by what mercury intrusion porosimetry measured Total pore volume, and the particle internal pore volume less than 0.3cc/gm that (ii) is measured by mercury intrusion porosimetry, and wherein described Intragranular hole is defined as aperture and is less than or equal toHole.
11. composite particles according to claim 10, wherein there is the composite particles (i) to be measured by mercury intrusion porosimetry Total pore volume more than 0cc/gm and less than about 0.98cc/gm, and (ii) by mercury intrusion porosimetry measures more than 0cc/gm and Particle internal pore volume less than about 0.28cc/gm.
12. the composite particles according to claim 10 or 11, wherein there is the composite particles (i) to be surveyed by mercury intrusion porosimetry The total pore volume of fixed about 0.15cc/gm to about 0.93cc/gm, and about 0.05cc/gm that (ii) is measured by mercury intrusion porosimetry To the particle internal pore volume of about 0.24cc/gm.
13. composite particles according to any one of claims 10 to 12, wherein the composite particles have (i) by pressure mercury The total pore volume for the about 0.25cc/gm to about 0.40cc/gm that gaging hole method measures, and pact that (ii) is measured by mercury intrusion porosimetry The particle internal pore volume of 0.08cc/gm to about 0.16cc/gm.
14. the composite particles according to any one of claim 10 to 13, wherein the composite particles have about 1.0 μm extremely About 100 μm of average particle size.
15. the composite particles according to any one of claim 10 to 14, wherein the composite particles have about 2.0 μm extremely About 60 μm of average particle size.
16. the composite particles according to any one of claim 10 to 15, wherein the composite particles have about 30.0 μm To about 50.0 μm of average particle size.
17. the composite particles according to any one of claim 10 to 16, wherein the porous inorganic particulate includes new sudden and violent The aggregate of the inner inorganic particle surface of dew, and the inside of (ii) described at least one active constituent and the new exposure without Machine particle surface contacts.
18. the composite particles according to any one of claim 10 to 17, wherein at least one active constituent includes Newly exposed inside active constituent surface, and at least one active constituent is via the inner inorganic of new exposure described in (i) Particle surface, the inside active constituent surface of (ii) described new exposure or (iii) (i) and (ii) the two and the porous, inorganic Particle contacts.
19. porous inorganic particulate according to any one of claim 1 to 8 or according to any one of claim 9 to 18 The composite particles, wherein the porous inorganic particulate has the average pore size of about 1.0nm to about 100.0nm.
20. porous inorganic particulate according to any one of claim 1 to 8 or according to any one of claim 9 to 19 The composite particles, wherein the porous inorganic particulate has the average pore size of about 2.0nm to about 50.0nm.
21. porous inorganic particulate according to any one of claim 1 to 8 or according to any one of claim 9 to 20 The composite particles, wherein the porous inorganic particulate has at least about 100m2/ g is up to 1500m2The BET of/g or bigger Granule surface area.
22. porous inorganic particulate according to any one of claim 1 to 8 or according to any one of claim 9 to 21 The composite particles, wherein the porous inorganic particulate has at least about 100m2/ g is up to 500m2The BET particle surfaces of/g Product.
23. porous inorganic particulate according to any one of claim 1 to 8 or according to any one of claim 9 to 22 The composite particles, wherein the porous inorganic particulate includes inorganic oxide particles.
24. porous inorganic particulate according to any one of claim 1 to 8 or according to any one of claim 9 to 23 The composite particles, wherein the porous inorganic particulate includes metal oxide particle.
25. porous inorganic particulate according to any one of claim 1 to 8 or according to any one of claim 9 to 24 The composite particles, wherein the inorganic particle includes silica dioxide granule.
26. porous inorganic particulate according to any one of claim 1 to 8 or according to any one of claim 9 to 25 The composite particles, wherein the porous inorganic particulate includes to be mechanically changed to provide newly exposure on it The silica dioxide granule on inner silica silicon particle surface.
27. the composite particles according to any one of claim 9 to 26, wherein at least one active constituent includes grain Shape active constituent.
28. the composite particles according to any one of claim 9 to 27, wherein at least one active constituent includes to live Property drug ingedient (API), agricultural chemicals, food additives or any combination of them.
29. the composite particles according to any one of claim 9 to 28, wherein at least one active constituent includes tool There is the active pharmaceutical ingredient (API) of tial crystalline structure.
30. the composite particles according to any one of claim 9 to 29, wherein at least one active constituent includes choosing From the active pharmaceutical ingredient (API) of brufen, ezetimibe or any combination of them.
31. the composite particles according to any one of claim 9 to 30, wherein (i) porous inorganic particulate and (ii) At least one active constituent is with about 100:1 to 1:Porous inorganic particulate in 100 ranges and at least one activity at The weight ratio divided exists.
32. the composite particles according to any one of claim 9 to 31, wherein (i) porous inorganic particulate and (ii) At least one active constituent is with about 10:1 to 1:Porous inorganic particulate in 10 ranges and at least one active constituent Weight ratio exist.
33. the composite particles according to any one of claim 9 to 32, wherein (i) porous inorganic particulate and (ii) At least one active constituent is with about 2:1 to 1:Porous inorganic particulate in 2 ranges and at least one active constituent Weight ratio exists.
34. porous inorganic particulate according to any one of claim 1 to 8 or according to any one of claim 9 to 33 The composite particles, wherein the particle includes the less than about water of 5.0 weight % of the total weight based on the particle.
35. porous inorganic particulate according to any one of claim 1 to 8 or according to any one of claim 9 to 34 The composite particles, wherein the particle includes the less than about water of 1.0 weight % of the total weight based on the particle.
36. the composite particles according to any one of claim 9 to 35, wherein the composite particles are substantially by described more Hole inorganic particle and at least one active constituent composition.
37. the composite particles according to any one of claim 9 to 36, wherein the composite particles are by the porous, inorganic Particle and at least one active constituent composition.
38. porous inorganic particulate according to any one of claim 1 to 8 or according to any one of claim 9 to 37 The composite particles, wherein the porous inorganic particulate via grinding or extrusion step by mechanically change have by Mercury intrusion porosimetry measure the porous inorganic particulate more than the total pore volume of 1.0cc/gm and formed.
39. a kind of method preparing porous inorganic particulate according to any one of claim 1 to 8, the method includes：
Initial porous inorganic particulate is provided, the initial porous inorganic particulate has the total pore volume measured by mercury intrusion porosimetry； And
The particle is set to be subjected to being enough to be formed the amount of newly exposed inner inorganic particle surface in dry solvent-free environment Then mechanical force allows at least part of the particle to consolidate or reunite again, initial more less than described to form total pore volume The porous inorganic particulate of the total pore volume of hole inorganic particle.
40. a kind of method preparing porous inorganic particulate, the method includes：
Initial porous inorganic particulate is provided, the initial porous inorganic particulate has is more than 0.1cc/ by what mercury intrusion porosimetry measured The total pore volume of gm；And
The particle is set to be subjected to being enough to be formed the amount of the porous inorganic particulate with following volumes in dry solvent-free environment Mechanical force：The total pore volume less than 1.0cc/gm measured by mercury intrusion porosimetry, and (ii) are measured by mercury intrusion porosimetry Particle internal pore volume less than 0.3cc/gm, wherein the particle endoporus is defined as aperture and is less than or equal toHole.
41. according to the method for claim 40, wherein there is the particle (i) to be more than 0cc/ by what mercury intrusion porosimetry measured Gm and total pore volume less than about 0.98cc/gm, and (ii) by mercury intrusion porosimetry measures more than 0cc/gm and being less than about The particle internal pore volume of 0.28cc/gm.
42. the method according to claim 40 or 41, wherein the particle has the pact that (i) is measured by mercury intrusion porosimetry The total pore volume of 0.15cc/gm to about 0.93cc/gm, and the about 0.05cc/gm that (ii) is measured by mercury intrusion porosimetry is to about The particle internal pore volume of 0.24cc/gm.
43. the method according to any one of claim 40 to 42, wherein there is the particle (i) to be surveyed by mercury intrusion porosimetry The total pore volume of fixed about 0.25cc/gm to about 0.40cc/gm, and about 0.08cc/gm that (ii) is measured by mercury intrusion porosimetry To the particle internal pore volume of about 0.16cc/gm.
44. the method according to any one of claim 40 to 43, wherein the particle has about 1.0 microns (μm) to about 100 μm of final average particle size.
45. the method according to any one of claim 40 to 44, wherein the particle is with about 2.0 μm to about 60 μm Final average particle size.
46. the method according to any one of claim 40 to 45, wherein the particle is with about 30.0 μm to about 50.0 μ The final average particle size of m.
47. a kind of method preparing the composite particles according to any one of claim 9 to 38, the method includes：
Initial porous inorganic particulate is provided, the initial porous inorganic particulate has the total pore volume measured by mercury intrusion porosimetry, And at least one active constituent；And
The particle and the active constituent is set to be subjected to being enough to be formed the amount of composite inorganic particle in dry solvent-free environment Mechanical force, the composite inorganic particle, which has, mechanically mixes active constituent in its hole, wherein the composite inorganic The total pore volume of particle is less than the total pore volume of the initial porous inorganic particulate.
48. a kind of method preparing composite particles, the method includes：
Porous inorganic particulate is provided, the porous inorganic particulate has the total hole more than 1.0cc/gm measured by mercury intrusion porosimetry Volume, and at least one active constituent；And
The particle and active constituent is set to be subjected to being enough to be formed the machine of compound porous inorganic particle in dry solvent-free environment Tool power, the compound porous inorganic particle has the active constituent mechanically mixed in its hole, wherein the composite particles It is less than by what mercury intrusion porosimetry measured with the total pore volume less than 1.0cc/gm measured by mercury intrusion porosimetry, and (ii) The particle internal pore volume of 0.3cc/gm, and the wherein described particle endoporus is defined as aperture and is less than or equal toHole.
49. according to the method for claim 48, wherein there is the composite particles (i) to be more than by what mercury intrusion porosimetry measured 0cc/gm and total pore volume less than about 0.98cc/gm, and (ii) by mercury intrusion porosimetry measures more than 0cc/gm and being less than The particle internal pore volume of about 0.28cc/gm.
50. the method according to claim 48 or 49, wherein there is the composite particles (i) to be measured by mercury intrusion porosimetry The total pore volume of about 0.15cc/gm to about 0.93cc/gm, and the about 0.05cc/gm that (ii) is measured by mercury intrusion porosimetry is to about The particle internal pore volume of 0.24cc/gm.
51. the method according to any one of claim 48 to 50, wherein the composite particles have (i) by pressure mercury gaging hole The total pore volume for the about 0.25cc/gm to about 0.40cc/gm that method measures, and pact that (ii) is measured by mercury intrusion porosimetry The particle internal pore volume of 0.08cc/gm to about 0.16cc/gm.
52. the method according to any one of claim 48 to 51, wherein the composite particles have about 1.0 μm to about 100 μm of final average particle size.
53. the method according to any one of claim 48 to 52, wherein the composite particles have about 2.0 μm to about 60 μm final average particle size.
54. the method according to any one of claim 48 to 53, wherein the composite particles have about 30.0 μm to about 50.0 μm of final average particle size.
55. the method according to any one of claim 47 to 54, it is subjected to step wherein described and causes by described at least one Kind of active constituent generates smaller active ingredient particle, the smaller active ingredient particle have newly exposed inside activity at Divide surface, and the composite particles include inner inorganic particle surface, (ii) the new exposure via new exposure described in (i) Inside active constituent surface or both (iii) (i) and (ii) and smaller active ingredient particle described in (ii) at least part At least part of smaller inorganic particle described in (i) of contact.
56. the method according to any one of claim 39 to 55, wherein the inorganic particle has about 1.0nm to about The average pore size of 100.0nm.
57. the method according to any one of claim 39 to 56, wherein the inorganic particle has about 2.0nm to about 50.0nm average pore size.
58. the method according to any one of claim 39 to 57, wherein the inorganic particle has at least about 100m2/g Up to 1500m2The BET granule surface areas of/g or bigger.
59. the method according to any one of claim 39 to 58, wherein the inorganic particle has about 100m2/ g is to about 500m2The BET granule surface areas of/g.
60. the method according to any one of claim 39 to 59, wherein the inorganic particle includes metallic particles.
61. the method according to any one of claim 39 to 60, wherein the inorganic particle includes mesoporous metal particle.
62. the method according to any one of claim 39 to 61, wherein the inorganic particle includes silica dioxide granule.
63. the method according to any one of claim 39 to 62, wherein being subjected to the described inorganic of the reduction step Particle includes silica dioxide granule.
64. the method according to any one of claim 47 to 63, wherein at least one active constituent includes activity Drug ingedient (API), agricultural chemicals, food additives or any combination of them.
65. the method according to any one of claim 47 to 64, wherein at least one active constituent includes to have The active pharmaceutical ingredient (API) of crystal structure.
66. the method according to any one of claim 47 to 65, wherein at least one active constituent includes to be selected from The active pharmaceutical ingredient (API) of brufen, ezetimibe or any combination of them.
67. the method according to any one of claim 47 to 66, wherein (i) inorganic particle and (ii) are described at least A kind of active constituent is with about 100:1 to 1:The weight ratio of inorganic particle and at least one active constituent in 100 ranges is deposited .
68. the method according to any one of claim 47 to 67, wherein (i) inorganic particle and (ii) are described at least A kind of active constituent is with about 10:1 to 1:The weight ratio of inorganic particle and at least one active constituent in 10 ranges exists.
69. the method according to any one of claim 47 to 68, wherein (i) inorganic particle and (ii) are described at least A kind of active constituent is with about 2:1 to 1:The weight ratio of inorganic particle and at least one active constituent in 2 ranges exists.
70. the method according to any one of claim 39 to 69, wherein the step that is subjected to is including the use of abrading-ball, injection Fluid or at least one extruder screw make the average particle size of the mixture of particle reduce.
71. the method according to any one of claim 39 to 70, wherein the step that is subjected to is including the use of abrading-ball, injection Fluid or at least one extruder screw make the particle reunite and be formed again.
72. the method according to any one of claim 39 to 71, wherein the step that is subjected to makes including the use of abrading-ball The average particle size of the mixture of grain reduces.
73. the method according to any one of claim 39 to 72, it is subjected to step wherein described and makes institute including the use of abrading-ball Particle is stated to reunite and formed again.
74. the method according to any one of claim 39 to 73, wherein described be subjected to step including grinding chamber and mill Occur in the vibrator of ball.
75. method according to claim 74, wherein the vibrator at about 12 hertz (Hz) to about 90 hertz (Hz) it is operated under the frequency in range.
76. the method according to claim 74 or 75, ground wherein making the vibrator operation less than about 25 minutes Time consuming.
77. the method according to any one of claim 39 to 76, wherein described be subjected to step including grinding chamber and mill Occur in the vibrator of ball, under frequency of the vibrator in about 20 hertz (Hz) to about 90 hertz of (Hz) ranges The milling time of operation less than about 25 minutes.
78. the method according to any one of claim 39 to 77, wherein described be subjected to step including grinding chamber and mill Occur in the vibrator of ball, under frequency of the vibrator in about 20 hertz (Hz) to about 40 hertz of (Hz) ranges The milling time of operation less than about 90 seconds.
79. the method according to any one of claim 39 to 78, wherein described be subjected to step including grinding chamber and mill Occur in the vibrator of ball, under frequency of the vibrator in about 20 hertz (Hz) to about 30 hertz of (Hz) ranges The milling time of operation less than about 60 seconds.
80. the method according to any one of claim 47 to 79, wherein the method further include：By the inorganic particle It is introduced into the vibrator including grinding chamber and abrading-ball at least one active constituent, the vibrator is about 20 It is operated under frequency in hertz (Hz) to about 90 hertz of (Hz) ranges.
81. the method according to any one of claim 70 to 80, wherein described (i) inorganic particle, (ii) at least one Active constituent and (iii) abrading-ball are with about 1 to 100:1 to 100:The weight ratio of (i) and (ii) and (iii) in 1 to 100 range are deposited .
82. the method according to any one of claim 70 to 81, wherein described (i) inorganic particle, (ii) at least one Active constituent and (iii) abrading-ball are with about 1 to 10:1 to 10:The weight ratio of (i) and (ii) and (iii) in 1 to 10 range exists.
83. the method according to any one of claim 39 to 69, wherein the step that is subjected to is including the use of injection fluid The average particle size of the mixture of particle is set to reduce.
84. according to the method described in any one of claim 39 to 69 and 83, wherein described be subjected to step including the use of injection Fluid makes the particle reunite and be formed again.
85. the method according to any one of claim 39 to 69 and 83 to 84, it is subjected to step wherein described and is ground in injection Occur in mill apparatus.
86. the method according to any one of claim 39 to 69, wherein described be subjected to step including the use of at least one Extruder screw makes the average particle size of the mixture of particle reduce.
87. according to the method described in any one of claim 39 to 69 and 86, wherein described be subjected to step including the use of at least One extruder screw makes the particle reunite and be formed again.
88. the method according to any one of claim 39 to 69 and 86 to 87, wherein described be subjected to step in extruder Middle generation.
89. the method according to any one of claim 47 to 88, wherein the method further include：
Before the reduction step, dry (i) described inorganic particle, (ii) described at least one active constituent or (iii) (i) and both (ii).
90. the method according to any one of claim 39 to 89, wherein the mixture of the particle includes based on described The total weight of the mixture of the particle less than about water of 5.0 weight %.
91. the method according to any one of claim 39 to 90, wherein the mixture of the particle includes based on described The total weight of the mixture of the particle less than about water of 1.0 weight %.
92. the method according to any one of claim 39 to 91, wherein the method reach in less than about 10 minutes Grain equilibrium, the grain equilibrium indicate to be further processed point when not leading to larger particles.
93. the method according to any one of claim 39 to 92, wherein the particle generated by the method has More than the final average particle size of the initial average particle size.
94. the method according to any one of claim 39 to 93, wherein described in the final average particle size ratio of the particle Initial average particle size greatly at least 1.0%.
95. the method according to any one of claim 39 to 94, wherein described in the final average particle size ratio of the particle Initial average particle size about 5.0% to about 25.0%.
96. the method according to any one of claim 47 to 95, wherein the finally average compound grain of the composite particles The initial average particle size greatly at least 1.0% of the degree inorganic particle more described than (i) or (ii) described at least one active constituent.
97. the method according to any one of claim 47 to 96, wherein the finally average compound grain of the composite particles The initial average particle size about 5.0% of the degree inorganic particle more described than (i) or (ii) described at least one active constituent is to about 25.0%.
98. porous inorganic particulate, the porous inorganic particulate is by the method shape according to any one of claim 39 to 97 At.
99. composite particles, the composite particles are formed by the method according to any one of claim 47 to 97.
100. a kind of pharmaceutical composition, described pharmaceutical composition includes compound according to any one of claim 9 to 38 Particle.
101. according to the pharmaceutical composition described in claim 100, described pharmaceutical composition is in selected from pill, tablet and capsule Form.
102. by the particle of the method formation according to any one of claim 39 to 97 or according to claims 1 to 38 It is used as by institute with the particle described in any one of 98 to 99 or the pharmaceutical composition according to claim 100 or 101 State the purposes of the reagent at least one active delivery to environment.
103. particle is as by the purposes of the reagent at least one active delivery to environment, the particle to include more Hole inorganic particle, the porous inorganic particulate have the total pore volume less than 1.0cc/gm that (i) is measured by mercury intrusion porosimetry, with And the particle internal pore volume less than 0.3cc/gm that (ii) is measured by mercury intrusion porosimetry, wherein the particle endoporus is defined as hole Diameter is less than or equal toHole.
104. according to the purposes of the particle described in claim 103, wherein there is the particle (i) to be measured by mercury intrusion porosimetry Total pore volume more than 0cc/gm and less than about 0.98cc/gm, and (ii) by mercury intrusion porosimetry measures more than 0cc/gm and Particle internal pore volume less than about 0.28cc/gm.
105. the purposes of the particle according to claim 103 or 104, wherein the particle has (i) by mercury intrusion porosimetry The total pore volume of the about 0.15cc/gm to about 0.93cc/gm of measurement, and about 0.05cc/ that (ii) is measured by mercury intrusion porosimetry The particle internal pore volume of gm to about 0.24cc/gm.
106. the purposes of the particle according to any one of claim 103 to 105, wherein the particle has (i) by pressing The total pore volume for the about 0.25cc/gm to about 0.40cc/gm that mercury gaging hole method measures, and pact that (ii) is measured by mercury intrusion porosimetry The particle internal pore volume of 0.08cc/gm to about 0.16cc/gm.
107. the purposes of the particle according to any one of claim 103 to 106, wherein the particle has about 1.0 μm To about 100 μm of average particle size.
108. the purposes of the particle according to any one of claim 103 to 107, wherein the particle has about 2.0 μm To about 60 μm of average particle size.
109. the purposes of the particle according to any one of claim 103 to 108, wherein the particle has about 30.0 μm To about 50.0 μm of average particle size.
110. the purposes of the particle according to any one of claim 103 to 109, wherein the particle includes to have on it There is the inorganic particle of newly exposed inner inorganic particle surface mechanically changed.
111. composite particles are as by the purposes of the reagent at least one active delivery to environment, described compound Grain include：(i) inorganic particle, and (ii) mechanically mix at least one of the hole of inorganic oxide particles activity Ingredient, wherein the composite particles have the total pore volume less than 1.0cc/gm that (i) is measured by mercury intrusion porosimetry, and (ii) The particle internal pore volume less than 0.3cc/gm measured by mercury intrusion porosimetry, wherein the particle endoporus is defined as aperture and is less than Or it is equal toHole.
112. according to the purposes of the composite particles described in claim 111, wherein the composite particles have (i) by pressure mercury gaging hole The total pore volume for being more than 0cc/gm and being less than about 0.98cc/gm that method measures, and (ii) are more than by what mercury intrusion porosimetry measured 0cc/gm and the particle internal pore volume for being less than about 0.28cc/gm.
113. the purposes of the composite particles according to claim 111 or 112, wherein the composite particles have (i) by pressing The total pore volume for the about 0.15cc/gm to about 0.93cc/gm that mercury gaging hole method measures, and pact that (ii) is measured by mercury intrusion porosimetry The particle internal pore volume of 0.05cc/gm to about 0.24cc/gm.
114. the purposes of the composite particles according to any one of claim 111 to 113, wherein the composite particles have (i) total pore volume of the about 0.25cc/gm to about 0.40cc/gm measured by mercury intrusion porosimetry, and (ii) by mercury intrusion porosimetry The particle internal pore volume of the about 0.08cc/gm to about 0.16cc/gm of measurement.
115. the purposes of the composite particles according to any one of claim 111 to 114, wherein the composite particles have About 1.0 μm to about 100 μm of average particle size.
116. the purposes of the composite particles according to any one of claim 111 to 115, wherein the composite particles have About 2.0 μm to about 60 μm of average particle size.
117. the purposes of the composite particles according to any one of claim 111 to 116, wherein the composite particles have About 30.0 μm to about 50.0 μm of average particle size.
118. the purposes of the composite particles according to any one of claim 111 to 117, wherein the porous, inorganic aoxidizes Composition granule includes the inner inorganic particle surface newly exposed, and (ii) described at least one active constituent and the new exposure Inner inorganic particle surface contacts.
119. the purposes of the composite particles according to any one of claim 111 to 118, wherein at least one activity Ingredient includes the inside active constituent surface newly exposed, and at least one active constituent is via new exposure described in (i) Both inner inorganic particle surface, the inside active constituent surface of (ii) described new exposure or (iii) (i) and (ii) with it is described Inorganic particle contacts.
120. the purposes of the particle according to any one of claim 103 to 110 or according in claim 111 to 119 The purposes of any one of them composite particles, wherein the inorganic particle has the average pore size of about 1.0nm to about 100.0nm.
121. the purposes of the particle according to any one of claim 103 to 110 or according in claim 111 to 120 The purposes of any one of them composite particles, wherein the inorganic particle has the average pore size of about 2.0nm to about 50.0nm.
122. the purposes of the particle according to any one of claim 103 to 110 or according in claim 111 to 121 The purposes of any one of them composite particles, wherein the inorganic particle has at least about 100m2/ g is up to 1500m2/ g or The BET granule surface areas of bigger.
123. the purposes of the particle according to any one of claim 103 to 110 or according in claim 111 to 122 The purposes of any one of them composite particles, wherein the inorganic particle has about 100m2/ g to about 400m2/ g or bigger BET granule surface areas.
124. the purposes of the particle according to any one of claim 103 to 110 or according in claim 111 to 123 The purposes of any one of them composite particles, wherein the inorganic particle includes inorganic oxide particles.
125. the purposes of the particle according to any one of claim 103 to 110 or according in claim 111 to 124 The purposes of any one of them composite particles, wherein the inorganic oxide particles include metal oxide particle.In a reality It applies in scheme, the metal oxide particle is mesoporous metal oxide particle.
126. the purposes of the particle according to any one of claim 103 to 110 or according in claim 111 to 125 The purposes of any one of them composite particles, wherein the inorganic particle includes silica dioxide granule.
127. the purposes of the particle according to any one of claim 103 to 110 or according in claim 111 to 126 The purposes of any one of them composite particles, wherein the inorganic particle includes via according to any one of claim 39 to 97 Silica dioxide granule prepared by the method.
128. the purposes of the composite particles according to any one of claim 111 to 127, wherein (i) inorganic particle (ii) described at least one active constituent is with about 100:1 to 1:Inorganic particle in 100 ranges and at least one activity The weight ratio of ingredient exists.
129. the purposes of the composite particles according to any one of claim 111 to 128, wherein (i) inorganic particle (ii) described at least one active constituent is with about 10:1 to 1:Inorganic particle in 10 ranges and at least one activity at The weight ratio divided exists.
130. the purposes of the composite particles according to any one of claim 111 to 129, wherein (i) inorganic particle (ii) described at least one active constituent is with about 2:1 to 1:Inorganic particle in 2 ranges and at least one active constituent Weight ratio exist.
131. the purposes of the composite particles according to any one of claim 111 to 130, wherein the composite particles include Total weight based on the composite particles less than about water of 5.0 weight %.
132. the purposes of the composite particles according to any one of claim 111 to 131, wherein the composite particles include Total weight based on the composite particles less than about water of 1.0 weight %.
133. the purposes of the composite particles according to any one of claim 111 to 132, wherein the composite particles are basic On be made of the inorganic particle and at least one active constituent.
134. the purposes of the composite particles according to any one of claim 111 to 133, wherein the composite particles are by institute State inorganic particle and at least one active constituent composition.
135. the purposes of the composite particles according to any one of claim 111 to 134, wherein at least one activity Ingredient includes active pharmaceutical ingredient (API).
136. the purposes of the composite particles according to any one of claim 111 to 135, wherein at least one activity Ingredient includes the active pharmaceutical ingredient (API) with tial crystalline structure.
137. the purposes of the composite particles according to any one of claim 111 to 136, wherein at least one activity Ingredient includes the active pharmaceutical ingredient (API) selected from brufen, ezetimibe or any combination of them.
138. particle according to any one of claim 103 to 110 or according to any one of claim 111 to 133 Purposes of the composite particles as dental product or oral care product.
139. particle according to any one of claim 103 to 110 or according to any one of claim 111 to 133 Purposes of the composite particles as skin-protection product.
140. particle according to any one of claim 103 to 110 or according to any one of claim 111 to 133 Purposes of the composite particles as cosmetic product.
141. particles according to any one of claim 103 to 110 or according to any one of claim 111 to 133 The composite particles provide the purposes of product as nutrition.
The purposes of 142. composite particles according to any one of claim 102 to 141, wherein the environment includes suffering from Person.
The purposes of 143. composite particles according to any one of claim 102 to 142, wherein the environment includes patient Enteron aisle.
The purposes of 144. composite particles according to any one of claim 111 to 133, wherein at least one activity Ingredient includes plant nutrient or insecticide.
The purposes of 145. composite particles according to any one of claim 102 to 133 and 144, wherein the environment packet Include plant or vicinity of plants.
146. particles according to any one of claim 103 to 110 or according to any one of claim 111 to 133 Purposes of the composite particles in catalyst application.
147. particles according to any one of claim 102 to 110 are appointed according in claim 111 to 133 and 146 The purposes of composite particles described in one, wherein the environment includes process reactor.
The purposes of 148. particle according to any one of claim 102 to 147, wherein the environment includes containing water ring Border.
The purposes of 149. composite particles according to any one of claim 111 to 148, wherein the composite particles make to At least one active constituent of few 50 weight % can be dissolved in the environment in 20 minutes.
The purposes of 150. composite particles according to any one of claim 111 to 149, wherein the composite particles make to At least one active constituent of few 50 weight % can be in 5 minutes dissolved in the environment.
A kind of 151. methods preparing porous inorganic particulate according to any one of claim 1 to 8, the method packet It includes：
Initial porous inorganic particulate is provided, the initial porous inorganic particulate has the total pore volume measured by mercury intrusion porosimetry； And
The particle is set to be subjected to being enough to be formed the amount of newly exposed inner inorganic particle surface in dry solvent-free environment Then mechanical force allows at least part of the particle to consolidate or reunite again, to form total pore volume different from described initial The porous inorganic particulate of the total pore volume of porous inorganic particulate.
A kind of 152. methods preparing the composite particles according to any one of claim 9 to 38, the method includes：
Initial porous inorganic particulate is provided, the initial porous inorganic particulate has the total pore volume measured by mercury intrusion porosimetry, And at least one active constituent；And
The particle and the active constituent is set to be subjected to being enough to be formed the amount of composite inorganic particle in dry solvent-free environment Mechanical force, the composite inorganic particle, which has, mechanically mixes active constituent in its hole, wherein the composite inorganic The total pore volume of particle is different from the total pore volume of the initial porous inorganic particulate.
CN201680069926.3A 2015-09-30 2016-09-30 The dry type amorphization of mechanical and chemical activation by Milling balance between AP and mesoporous silica Pending CN108601844A (en)

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US11478424B2 (en) 2022-10-25
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